Diseases

Three human diseases, dyskeratosis congenita (DKC), aplastic anemia (AA), and idiopathic pulmonary fibrosis (IPF), have been linked to mutations within the genes that encode for the two telomerase essential core components, telomerase RNA (TR) and telomerase reverse transcriptase (TERT); telomerase-associated proteins, DKC1 encodes for dyskerin and Nola3 encodes for Nop10; and recently to one of the six proteins that for the shelterin complex, TINF2 encodes for TIN2. Heterogeneous mutations show that even half the dose of telomerase is insufficient to maintain telomere length, resulting in erosion and loss of function, senescence, and apoptosis. The maintenance of telomere length in highly prolific cells, germline and stem cells, is crucial for the preservation of high populations and human health. In general point mutations, which leads to a single amino acid substitution, are better tolerated than frame shift and splicing junction mutations, limiting but not abolishing telomerase activity. The toleration of reduction and loss of telomerase function decreases with each subsequent generation. This anticipation, or progression of symptoms within the next generation, is characteristic of telomerase-deficiency diseases. The telomeres of the parental generation erode and when passed to their offspring begin this generation with shorter telomeres. The increase in severity of symptoms is linked with the progressive decrease of telomere length.

Dyskeratosis congenita (DKC) is an inherited disorder with clinical manifestations of skin hyperpigmentation (dark patches of skin), oral leukoplakia (white spots inside the mouth), and nail dystrophy (lack of nails). The majority of deaths occur from bone marrow failure, immunodeficiency, pulmonary complications, and malignancies. The X-linked recessive form has severe clinical presentations and caused by mutations found within the DKC1 gene that encodes for the dyskerin protein. The autosomal dominant form of the disease has been shown to be caused by mutations within the genes that encode TR as well as TERT. The autosomal recessive form of the disease has been shown to be caused by a mutation within Nola3, the gene that codes for Nop10. These mutations cause a reduction of telomerase activity leading to a limitation in stem cell capacity for proliferation. This reduction in proliferative capacity for high turnover cells leads in low counts for blood and immune cells, resulting in aplastic anemia. Bone marrow failure, brought on by the aplastic anemia, is the most common cause of death for patients with DKC. Families with this disease show anticipation, or the worsening of symptoms in subsequent generations because each generation begins with shorter telomeres than the previous Vulliamy et al, 2006.

Aplastic anemia (AA) is characteristically an acquired disease, however, there are rare constitutional forms of the disease that are found in patients with a strong familial history of various blood diseases. The disease has is connected with mutations with the genes that encode TR and TERT. This constitutional form of bone marrow failure is defined by low peripheral blood cell counts, hypocellular bone marrow, does not respond to immunosuppressive therapy, and included typical physical anomalies. The constitutional has associated with patients with DKC, however, there are cases lacking symptoms of DKC. The most common cause of death is due to bone marrow failure Fogarty et al, 2003.

Idiopathic pulmonary fibrosis (IPF) is a specific form of plumonary fibrosis with unknown cause, Plumonary fibrosis involves fibrotic lesion and scarring of the lung. The build up of excess scar tissue in the lungs results in reduced lung volume. The symptoms that typify the disease are chronic cough and shortness of breath. Some familiar types of IPF are caused by mutations in the genes that encode TR and TERT Armanios et al, 2007.

A standard nomenclature is used throughout the online database for consistency and clarity. Mutations designated according to the guidelines and recommendations for mutation nomenclature from the Human Genome Variation Society (HGVS). The nucleotides are numbered according to the coding DNA reference sequence, intronic positions are numbered as an addition to the last nucleotide from the preceding exon or as a difference from the first nucleotide from the proceeding exon. The (?) indicates uncertainty in the description of the mutation while frame shifts are described by the first affected amino acid and from this position the number of amino acids to the stop codon.

TR	TERC	TER	TER1	TLC1
TERT	TRT	Est2	p123	TP2	TCS1
Gar1	Nola1
NHP2	Nola2	L7Ae
Nop10	Nola3
dyskerin	Nola4	Cbf5	DKC1	NAP57
DnaK	hsp70
Est1A	Smg6
Est1B	Smg5
TRF1	TERF1	TRBF1	TRF	PIN2	FLJ41416
TRF2	TERF2	TRBF2
Pot1	TEBPα
TINF2	TIN2
Rap1	TERF2IP	DRIP5
TPP1	TEBPβ	CLN2	GIG1	LPIC
MDV	GaHV (Gallid herpesvirus)

Listed in gold is the nomenclature in use within the database with other common names and homologs to the right.

TR

TR mutations (autosomal dominant DKC, AA, IPF)

Numerous mutations causing nucleotide substitution, additions, and deletions have been documented within TR, the RNA component of the telomerase ribonucleoprotein (RNP), that have been connected with human diseases. TR contains the template that encodes for telomeric repeats and binds to telomerase reverse transcriptase (TERT) for DNA synthesis. Three domains characterize TR, pseudoknot that includes the template, conserved regions 4 and 5 (CR4-CR5), and ScaRNA domain for nuclear recruitment.

The above secondary structure for the 451 nt RNA component of the telomerase ribonucleoprotein (RNP) has indicated the location of mutations known to cause human diseases. The primary nucleotide sequence is in black, point mutations are colored red, while deletion mutations are shaded blue, and both are labeled. The Genbank accession number used is NR_001566 for the RNA sequence. Below is a description of the locations within the nucleotide sequence, the characteristic clinical presentations, and original literature citations that are linked to the published online journal for known mutations within the RNA component of telomerase. The mutations are organized by domain from the 5'-terminus to the 3'-terminus.

TR mutations

Domains	Mutation	Region	Presentation	References
Promoter	c.1-22C>U		Pulmonary Fibrosis	Justet et al, 2021
	c.-771A>G	n/a	myelodysplastic syndrome	Carroll et al, 2011
	c.-714insC	n/a	myelodysplastic sydrome	Carroll et al, 2011
	c.-240delCT	n/a	myelodysplastic syndrome	Field et al, 2006
	c.-99C>G	n/a	paroxysmal nocturnal hemoglobinuria, menorrhagia, anemia, and thrombocytopenia	Keith et al, 2004 Ortmann et al, 2006
Pseudoknot	r.1-22C>U		Pulmonary Fibrosis	Borie et al, 2015
	r.2g>c	5' end	aplastic anemia	Marrone et al, 2007.1
	r.17G>A	5' end	Myelodysplastic syndrome / Acute myeloid leukemia	Schratz et al, 2020
	r.23 G>C		Pulmonary Fibrosis	Justet et al, 2021
	r.28_34del7	P1a	aplastic anemia	Xin et al, 2007
	r.30G>A		Pulmonary Fibrosis	Justet et al, 2021
	r.35C>U	NA	Pulmonary Fibrosis	Justet et al, 2021
	r.35c>u	P1b	hypoplastic myelodysplastic syndrome	Du et al, 2009
	r.36c>u	P1b	aplastic anemia	Vulliamy et al, 2011
	r.37a>g	P1b	autosomal dominant dyskeratosis congenita, idiopathic pulmonary fibrosis, dyspnea, aplastic anemia, and hepatic cirrhosis	Ly et al, 2005.2 Tsakiri et al, 2007 Calado et al, 2011 Han et al, 2009
	r.48a>g	Template	dyskeratosis congenita	Vulliamy et al, 2006
	r.52_55delcuaa	Template	myelodysplasia and dyskeratosis congenita	Vulliamy et al, 2006
	r.52_86del35	Template	pulmonary fibrosis	Marrone et al, 2007.1
	r.54_57delaacu	Template	dyskeratosis congenita	Jongmans et al, 2012
	r.58g>a	template flanking	polymorphism	Vulliamy et al, 2002 Yamaguchi et al, 2003 Marrone et al, 2004
	r.67g>a	P2a.1	aplastic anemia	Vulliamy et al, 2011
	r.72c>g	P2a.1	aplastic anemia	Vulliamy et al, 2002
	r.73g>u	P2a.1	dyskeratosis congenita	Yamaguchi et al, 2015
	r.79delc	P2a	aplastic anemia	Vulliamy et al, 2006
	r.80u>a	P2a	idiopathic pulmonary fibrosis	Stanley et al, 2015
	r.83u>g	P2a	aplastic anemia, myelodysplastic syndrome	Vulliamy et al, 2011
	r.91G>C		Pulmonary Fibrosis	Justet et al, 2021
	r.93g>c	P2b	dyskeratosis congenita	Collopy et al, 2015
	r.95_96delgc	P3	dyskeratosis congenita	Vulliamy et al, 2011
	r.96_97delcu	P2b	autosomal dominant dyskeratosis congenita	Vulliamy et al, 2004
	r.98g>a	P2b	idiopathic pulmonary fibrosis	Armanios et al, 2007
	r.100u>a	P2b flanking	dyskeratosis congenita	Du et al, 2009
	r.107g>u	P3	aplastic anemia	Vulliamy et al, 2011
	r.107_108gc>ag	P3	autosomal dominant dyskeratosis congenita	Vulliamy et al, 2001
	r.108c>u	P3	idiopathic pulmonary fibrosis	Dai et al, 2014
	r. 109_123del15	P3_P2b	pancytopenia	Calado et al, 2009.2
	r.110_113delGACU		Pulmonary Fibrosis	Justet et al, 2021
	r.110_113delgacu	P3	aplastic anemia, myelodysplasia and leukemia	Vulliamy et al, 2002 Marrone et al, 2007.1
	r.116c>u	P2b	aplastic anemia and thrombocytopenia	Fogarty et al, 2003 Ortmann et al, 2006
	r.117a>c	P2b	aplastic anemia	Ly et al, 2005.1
	r.126a>g	P2a	aplastic anemia	Vulliamy et al, 2011
	r.129_140delinsgu	P2a	dyskeratosis congenita	Collopy et al, 2015
	r.135G>C		Pulmonary Fibrosis	Justet et al, 2021 Borie et al, 2015
	r.143g>a	P2a.1	autosomal dominant dyskeratosis congenita and aplastic anemia	Vulliamy et al, 2004 Parry et al, 2011
	r.164A>C	NA	Pulmonary Fibrosis	Justet et al, 2021
	r.170C>A	NA	Pulmonary Fibrosis	Justet et al, 2021
	r.176a>c	P3	aplastic anemia	Vulliamy et al, 2011
	r.178g>a	P3	aplastic anemia	Marrone et al, 2007.1
	r.180c>u	P3	aplastic anemia	Marrone et al, 2007.1
	r.182delG		Pulmonary Fibrosis	Justet et al, 2021 Borie et al, 2016
	r.182g>c	P3	pleuroparenchymal fibroelastosis	Newton et al, 2016
	r.182g>a	P3	aplastic anemia	Vulliamy et al, 2011
	r.200_201 delinsAG	NA	Pulmonary Fibrosis	Justet et al, 2021
	r.202u>g	p1a	dyskeratosis congenita	Collopy et al, 2015
	r.204c>g	P1a	aplastic anemia	Fogarty et al, 2003
	r.205c>u	p1a	dyskeratosis congenita	Collopy et al, 2015
Hypervariable	r.212c>g	P4	dyskeratosis congenita, myelodysplastic syndrome, and aplastic anemia	Collopy et al, 2015 Kirwan et al, 2009
	r.216_229del14	P4.1	autosomal dominant dyskeratosis congenita	Ly et al, 2005.2
	r.228g>a	P4.1	polymorphism	Yamaguchi et al, 2003 Marrone et al, 2004
	r.235C>G		Pulmonary Fibrosis	Justet et al, 2021
	r.236C>U		Pulmonary Fibrosis	Borie et al, 2016
	r.242c>u	P5	hoyeraal hreidarsson syndrome	Vulliamy et al, 2011
CR4-CR5	r.257g>u	P6b	bone marrow failure	Alder et al, 2018
	r.287c>g	P6b	myelodysplastic syndrome	Vulliamy et al, 2011
	r.305g>a	P6.1	aplastic anemia	Yamaguchi et al, 2003
	r.309g>u	P6.1	acute myeloid leukaemia	Holme et al, 2012
	r.316_451del136	J6/5 to Box ACA	autosomal dominant dyskeratosis congenita	Vulliamy et al, 2004
	r.319g>a	P5	liver fibrosis	Boyraz et al, 2016
	r.322g>a	P5	myelodysplasia and refractory anemia	Yamaguchi et al, 2003
	r.323c>u	P5	myelodysplastic syndrome	Takeughi et al, 2007
	r.323C>G		Pulmonary Fibrosis	Justet et al, 2021
	r.325g>u	P5	idiopathic pulmonary fibrosis	Alder et al, 2008
Hypervariable	r.341_360del20	P4.1_P4.2	pancytopenia	Calado et al, , 2009.2
ScaRNA	r.375_377delgga	Box H	idiopathic pulmonary fibrosis	Alder et al, 2011
	r.377a>g	Box H	aplastic anemia, myelodysplastic syndrome	Vulliamy et al, 2011 Ueda et al, 2014
	r.378_451del74	Box H to Box ACA	autosomal dominant dyskeratosis congenita	Vulliamy et al, 2001
	r.389_390delcc	P7b	essential thrombocythemia	Ly et al, 2005.1
	r.408c>g	P8b	autosomal dominant dyskeratosis congenita	Vulliamy et al, 2001
	r.448A>U		Pulmonary Fibrosis (pneumocystosis)	Justet et al, 2021 Borie et al, 2017
	r.448A>G		Pulmonary Fibrosis	Justet et al, 2021
	r.448a>g	Box ACA	dyskeratosis congenita	Collopy et al, 2015
3' UTR	c.467u>c	3' UTR	aplastic anemia	Yamaguchi et al, 2003

TERT

TERT mutations (autosomal dominant DKC, AA, IPF)

Numerous mutations causing amino acid substitution, additions, deletions, and frame shifts within TERT, the essential protein component of the telomerase ribonucleoprotein (RNP), have been connected with human diseases. TERT contains the catalytic site for the synthesis of telomeric repeats from the RNA template. TERT is composed of three domains, N-terminal extension (NTE) that contains RNA-interaction domains 1 and 2 (RID1 and RID2), reverse transcription domain (RT) where nucleotide transfer occurs, and a C-terminal extension (CTE) for processivity and localization.

The above structural organizational scheme for the various motifs with the three domains of the TERT protein has indicated the locations of mutations known to cause human diseases. The black line represents the mRNA sequence of 4015 nt with the untranslated regions (UTR) labeled and the grey box corresponds to the protein sequence. The individual motifs are labeled and NTE is denoted by green, CTE by orange, and the central RT domain by blue boxes. The Genbank accession numbers used are NT_006576 for the 41881 bp gene and NM_198253 for the cDNA and amino acid sequences. Below is the 1132 amino acid sequence for TERT protein with the motifs labeled and colored by domain. The mutated residues are colored red and the change in amino acids is labeled.

1132 amino acid sequence for TERT protein

Below is a description of the locations within the nucleotide and protein sequence, the amino acid substitutions, the characteristic clinical presentations, and original literature citations that are linked to the published online journal for known mutations within the telomerase protein TERT. The cDNA sequence is used for the nucleotide sequence. The mutations are organized by domain from the N-terminus to the C-terminus and grouped by domain.

TERT mutations

Domains	Mutation	AA substitution	Motif	Presentation	References
N-Terminal	c.22_43dup22	p.Arg15Profs*184	n/a	Pulmonary fibrosis	Borie et al, 2016
	c.55C>T	p.Arg19Cys	n/a	Pulmonary fibrosis	Borie et al, 2016
	c.97C>T	p.Pro33Ser	n/a	idiopathic pulmonary fibrosis and fibrosis	Tsakiri et al, 2007
	r.110_113delGACT		n/a	Pulmonary fibrosis	Borie et al, 2015
	c.164T>A	p.Leu55Gln	n/a	idiopathic pulmonary fibrosis	Armanios et al, 2007
	c.166G>C	p.Val56Leu	n/a	aplastic anemia	Vulliamy et al, 2011
	c.193C>G	p.Pro65Ala	GQ	acute myeloid leukemia	Calado et al, 2009
	c.228C>A	p.Cys76*	GQ	Pulmonary fibrosis	Borie et al, 2016
	c.232A>T	p.Lys78*	GQ	Pulmonary fibrosis	Justet et al, 2021
	c.248G>C	p.Arg83Pro	GQ	aplastic anemia, myelodysplastic syndrome	Vulliamy et al, 2011
	c.250C>T	p.(?)	GQ	head and neck ucosal melanoma	Sari et al, 2016
	c.277+1G>A	n/a	IVS1	idiopathic pulmonary fibrosis	Armanios et al, 2007
	c.299G>A	p.Gly100Asp	GQ	Pulmonary fibrosis	Justet et al, 2021
	c.(?)	p.Gly106Trp	GQ	cryptic dyskeratosis congenita	Yamaguchi et al, 2015
	c.329G>C	p.Gly110Ala	GQ	dyskeratosis congenita	Collopy et al, 2015
	c.(334_336)delC	p.Pro112ProfsX16	GQ	idiopathic pulmonary fibrosis	Armanios et al, 2007
	c.	p.Thr116Ile	GQ	Myelodysplastic syndrome	Schratz et al, 2020
	c.336dupC	p.Glu113Argfs*79	GQ	Pulmonary fibrosis	Justet et al, 2021
	c.345C>G	p.Phe115Leu	GQ	Myelodysplastic syndrome and Acute myeloid leukemia	Schratz et al, 2021
	c.355G>A	p.Val119Met	GQ	dyskeratosis congenita	Collopy et al, 2015
	c.395G>A	p.Arg132Gln	GQ	Pulmonary fibrosis	Borie et al, 2016 Justet et al, 2021
	c.(?)	p.Gly135Glu	GQ	hepatopulmonary syndrome	Gorgy et al, 2015
	c.430G>A	p.Val144Met	GQ	idiopathic pulmonary fibrosis and pleuroparenchymal fibroelastosis	Tsakiri et al, 2007 Newton et al, 2016
	c.446T>A	p.Leu149Gln	GQ	Pulmonary fibrosis	Justet et al, 2021
	c.508G>A	p.Val170Met	GQ	aplastic anemia and pulmonary fibrosis	Parry et al, 2011
	c.515G>A	p.Gly172Glu	GQ	Pulmonary fibrosis	Justet et al, 2021
	c.(?)	p.Val170Leu	GQ	idiopathic pulmonary fibrosis	Alder et al, 2018
	c.604G>A	p.Ala202Thr	n/a	aplastic anemia	Vulliamy et al, 2005 Yamaguchi et al, 2005
	c.779G>A	p.Gly260Asp	n/a	aplastic anemia	Calado et al, 2009.1
	c.(?)	p.Ala243Val	n/a	hepatocellular carcinoma	Donaires et al, 2017
	c.1849C>T	p.Ala279Thr	n/a	polymorphism	Du et al, 2009 Alder et al, 2008 Vulliamy et al, 2006
	c.(?)	p.Glu280Lys	n/a	dyskeratosis congenita	Yamaguchi et al, 2015
	c.895G>A	p.Val299Met	n/a	acute myeloid leukemia	Calado et al, 2009
	c.896G>A	p.(?)	n/a	acute myeloid leukaemia	Yan et al, 2012
	c.1002_1004del	p.334_335del	n/a	dyskeratosis congenita	Yamaguchi et al, 2015
	c.1062A>T	p.(?)	n/a	acute myeloid leukaemia	Aref et al, 2014
	c.1079C>G	p.(?)	n/a	acute myeloid leukaemia	Yan et al, 2012
	c.1103C>T	p.Ser368Phe	n/a	pancytopenia, aplastic anemia, pulmonary fibrosis	Calado et al, 2009.2
	c.1141C>T	p.Arg281Cys	n/a	dyskeratosis congenita	Collopy et al, 2015
	c.1141C>G	p.Arg281Gly	n/a	dyskeratosis congenita	Collopy et al, 2015
	c.1142G>C	p.Arg381Pro	n/a	dyskeratosis congenita	Vulliamy et al, 2011
	c.1215C>G	p.Tyr405*	CP	Pulmonary fibrosis	Justet et al, 2021
	c.1234C>T	p.His412Tyr	CP	polymorphism/aplastic anemia/myelodysplastic syndrome/idiopathic pulmonary fibrosis	Alder et al, 2008 Yamaguchi et al, 2005 Juge et al, 2017
	c.1321_1323delGAG	p.Glu441del	n/a	polymorphism/hepatic cirrhosis	Yamaguchi et al, 2005 Calado et al, 2011
	c.1336_1337insC	p.Arg446ProfsX93	n/a	dyskeratosis congenita	Collopy et al, 2015
	c.1336dupC	p.Arg446Profs*93	n/a	Dyskeratosis congenita, pulmonary fibrosis	Justet et al, 2021
	c.1432T>C	p.Trp478Arg	QFP	Pulmonary fibrosis	Justet et al, 2021
	c.1451G>C	p.(?)	QFP	acute myeloid leukaemia	Yan et al, 2012
	c.1456C>T	p.Arg486Cys	QFP	idiopathic pulmonary fibrosis	Tsakiri et al, 2007
	c.(?)	p.Phe487Leu	QFP	liver disease and bone marrow failure	Alder et al, 2018
	c.1511C>T	p.Ser504Leu	QFP	Pulmonary fibrosis	Borie et al, 2016 Justet et al, 2021
	c.1565G>A	p.Arg522Lys	n/a	acute myeloid leukemia	Calado et al, 2009
	c.1570C>G	p.Pro524Ala	n/a	aplastic anemia	Collopy et al, 2014
	c.1584T>G	p.Cys528Trp	n/a	Pulmonary fibrosis	Snetselaar et al, 2017 Justet et al, 2021
	c.1589C>T	p.Pro530Leu	n/a	hoyeraal-hreidarsson syndrome/dyskeratosis congenita/hepatic cirrhosis/pulmonary fibrosis	Vogiatzi et al, 2013 Carrillo et al, 2012 Calado et al, 2011 Maryoung et al, 2017
	c.1604G>A	p.Arg535His	n/a	Myelodysplastic syndrome	Schratz et al, 2020
	c.1630T>C	p.Phe544Leu	T	Pulmonary fibrosis	Borie et al, 2016 Justet et al, 2021 Borie et al, 2015
	c.1692G>A	p.Thr564Thr	T	Pulmonary fibrosis	Borie et al , 2016
	c.1698_1700delCAC	p.Thr567del	T	Pulmonary fibrosis	Snetselaar et al, 2017 Justet et al, 2021
	c.1710G>C	p.Lys570Asn	T	Pulmonary fibrosis	Borie et al, 2015 Justet et al, 2021
	c.1710G>(T_C)	p.Lys570Asn	T	Heterozygote presents as aplastic anemia	Xin et al, 2007
	c.1710G>(T_C)	p.Lys570Asn	T	Homozygote presents as Hoyeraal Hreidarsson syndrome	Gramatges et al , 2013
	c.1729C>T	p.Arg577Trp	T	Pulmonary fibrosis	Justet et al, 2021
	c.(?)	p.Asn571Ser	T	pulmonary fibrosis and bone marrow failure	Alder et al, 2018
c.1743delG	p.Trp581X	QFP	dyskeratosis congenita	Collopy et al, 2015
c.1769+1G>A	n/a	IVS	dyskeratosis congenita	Collopy et al, 2015
c.1805C>T	p.Ser602Leu	n/a	Pulmonary fibrosis	Justet et al, 2021
Reverse transcriptase	c.(?)	p.Arg622His	1	idiopathic pulmonary fibrosis	Dai et al, 2014
	c.1828C>T	p.Arg610Trp	n/a	Pulmonary fibrosis	Nunes et al, 2017 Justet et al, 2021
	c.1864C>T	p.Arg622Cys	1	Pulmonary fibrosis	Borie et al, 2016 Justet et al, 2021
	c.1882G>A	p.Asp628Asn	1	Pulmonary fibrosis	Justet et al, 2021
	c.1885G>C	p.Gly629Arg	1	idiopathic pulmonary fibrosis	Petrovski et al, 2017
	c.1892G>A	p.Arg631Gln	2	pulmonary fibrosis	Diaz de Leon et al, 2010
	c.1895C>T	p.Pro632Leu	2	pulmonary fibrosis	Maryoung et al, 2017
	c.1895C>G	p.Pro632Arg	2	cryptic dyskeratosis congenita	Yamaguchi et al, 2015
	c.1928G>C	p.Arg643Thr	n/a	Myelodysplastic syndrome	Schratz et al, 2020
	c.1989G>C	p.Ser663Arg	3a	idiopathic pulmonary fibrosis	Petrovski et al, 2017
	c.(?)	p.Val664Leu	3a	bone marrow failure and idiopathic pulmonary fibrosis	Alder et al, 2018
	c.2005C>T	p.Arg669Trp	3a	Pulmonary fibrosis	Newton et al, 2016 Snetselaar et al, 2017 Van der vis et al, 2020 Justet et al, 2021
	c.2011C>T	p.Arg671Trp	3b	Pulmonary fibrosis	Diaz de Leon et al, 2010 Snetselaar et al, 2017 Justet et al, 2021
	c.	p.Arg671Gly	3b	Myelodysplastic syndrome	Schratz et al, 2020
	c.2033C>A	p.Ala678Asp	3b	pulmonary fibrosis	Chambers et al, 2012
	c.2045G>A	p.Gly682Asp	3b	aplastic anemia	Liang et al, 2006
	c.2053G>A	p.Asp685Asn	3b	Myelodysplastic syndrome	Schratz et al, 2020
	c.2058C>G	p.Ile686Met	3b	Myelodysplastic syndrome	Schratz et al, 2020
	c.2062C>G	p.Glu668Asp	3a	cyrptogenic cirrhosis	Valenti et al, 2013
	c.2069G>C	p.Trp690Ser	3c	idiopathic pulmonary fibrosis	Petrovski et al, 2017
	c.2080G>A	p.Val694Met	3c	Pulmonary fibrosis, Cancer	Yamaguchi et al, 2005 Schratz et al, 2020 Justet et al, 2021
	c.2081C>T	p.Val694Glu	3c	idiopathic pulmonary fibrosis	Petrovski et al, 2017
	c.2092C>T	p.Arg698Trp	3c	dyskeratosis congenita	Carrillo et al, 2012
	c.2093G>A	p.Arg698Gln	3c	dyskeratosis congenita	Carrillo et al, 2012
	c.2093G>A	p.Arg698Gln	3c	Pulmonary fibrosis	Borie et al, 2016
	c.2105C>T	p.Pro702Leu	n/a	pulmonary fibrosis	Cronkhite et al, 2008
	c.2105C>T	p.Pro702Leu	n/a	Pulmonary fibrosis	Borie et al, 2016
	c.2110C>T	p.Pro704Ser	n/a	autosomal dominant dyskeratosis congenita/aplastic anemia/idiopathic pulmonary fibrosis/myelodysplastic syndrome	Du et al, 2009 Du et al, 2008 Petrovski et al, 2017 Keel et al, 2016 Schratz et al, 2020
	c.2113G>C	p.Glu705Gln	n/a	dyskeratosis congenita	Collopy et al, 2015
	c.2146G>A	p.Ala716Thr	A	Aplastic anemia, pulmonary fibrosis	Parry et al, 2011 Borie et al, 2016 Snetselaar et al, 2017 Justet et al, 2021
	c.2147C>T	p.Ala716Val	A	severe pancytopenia and aplastic anemia	Du et al, 2009
	c.2147C>T	p.Ala716Val	A	Pulmonary fibrosis	Vulliamy et al, 2011 Justet et al, 2021
	c.2152G>A	p.Asp718Asn	A	dyskeratosis congenita	Vulliamy et al, 2011
	c.2159T>C	p.Ile720Thr	n/a	Pulmonary fibrosis	Borie et al, 2016
	c.2162C>G	p.Pro721Arg	n/a	autosomal recessive dyskeratosis congenita	Vulliamy et al, 2006
	c.(?)	p.Gln722X	IFDa	bone marrow failure	Alder et al, 2018
	c.2173C>T	p.Leu714Phe	n/a	aplastic anemia	Collopy et al, 2014
	c.2177C>T	p.Thr726Met	IFDa	aplastic anemia	Liang et al, 2006
	c.2224C>T, c.2655-47_2659dup	p.Arg742Cys p.Leu887Argfs*16	n/a	Pulmonary fibrosis	Justet et al, 2021
	c.2225G>A	p.Arg742His	IFDb	Pulmonary fibrosis	Petrovski et al, 2017 Justet et al, 2021
	c.2240delT	p.Val747AlafsX20	IFDb	idiopathic pulmonary fibrosis	Tsakiri et al, 2007
	c.2267G>T	p.Arg756Leu	IFDb	Pulmonary fibrosis	Borie et al, 2016 Justet et al, 2021
	c.2287-2A>G		IFDb	Pulmonary fibrosis	Borie et al, 2016 Justet et al, 2021
	c.2287-2A>C	p.Arg756Leu	n/a	Pulmonary fibrosis	Borie et al, 2016 Justet et al, 2021
	c.2315A>G	p.Tyr772Cys	IFDb	aplastic anemia	Yamaguchi, 2005
	c.2318T>C	p.Met773Thr	IFDb	dyskeratosis congenita	Collopy et al, 2015
	c.2321G>T	p.Arg774Leu	IFDb	Pulmonary fibrosis	Justet et al, 2021
	c.2329G>A	p.Val777Leu	IFDb	dyskeratosis congenita, idiopathic pulmonary fibrosis	Collopy et al, 2015 Dai et al, 2014
	c.2354C>T	p.Pro785Leu	IFDb	acute myeloid leukaemia	Holme et al, 2012
	c.2377G>A	p.Glu793Lys	IFDb	Pulmonary fibrosis	Justet et al, 2021
	c.2383-2A>G	n/a	IVS	idiopathic pulmonary fibrosis	Juge et al, 2017
	c.2431C>T	p.Arg811Cys	IFDc	autosomal recessive dyskeratosis congenita	Marrone et al, 2007.2
	c.2431C>T	p.Arg811Cys	IFDc	Pulmonary fibrosis	Marrone et al, 2007.2 Justet et al, 2021
	c.2446C>G	p.His816Asp	B	Pulmonary fibrosis	Justet et al, 2021
	c.2456G>A	p.Arg819His	B	Pulmonary fibrosis	Justet et al, 2021
	c.2468+6T>G	n/a	B	Pulmonary fibrosis	Justet et al, 2021
	c.2474A>G	p.Tyr825Cys	B	dyskeratosis congenita	Collopy et al, 2015
	c.?	p.Val826Ser	B	Myelodysplastic syndrome	Schratz et al, 2020
	c.2516C>T	p.Thr839Met	B	Pulmonary fibrosis	Justet et al, 2021
	c.2521C>T	p.Leu841Phe	B	pulmonary fibrosis	Parry et al, 2011
	c.2537A>G	p.Tyr846Cys	B	aplastic anemia	Du et al, 2008
	c.2542G>A	p.Asp848Asn	B	Pulmonary fibrosis	Justet et al, 2021
	c.2572C>T	p.Arg858Trp	n/a	pulmonary fibrosis, liver disease and bone marrow failure	Newton et al, 2016
	c.2581G>A	p.Gly861Arg	n/a	myelodysplastic syndrome	Vulliamy et al, 2011 Schratz et al, 2020
c.2583-2A>C	p.Leu862_Leu884del	IVS9	idiopathic pulmonary fibrosis	Armanios et al, 2007
c.2593C>T	p.Arg865Cys	C	idiopathic pulmonary fibrosis	Tsakiri et al, 2007
c.2594G>A	p.Arg865His	C	idiopathic pulmonary fibrosis, fibrosis, and aplastic anemia	Tsakiri et al, 2007 Diaz de Leon et al, 2010 Newton et al, 2016 Justet et al, 2021
c.(?)	p.Arg865Ala	C	idiopathic pulmonary fibrosis	Newton et al, 2016
c.2599G>A	p.Val867Met	C	pulmonary fibrosis	Diaz de Leon et al, 2010
c.2603A>G	p.Asp868Gly	C	dyskeratosis congenita	Sharma et al, 2014
c.(?)	p.Thr874Arg	C	idiopathic pulmonary fibrosis	Newton et al, 2016
c.2620A>G	p.Thr874Ala	C	idiopathic pulmonary fibrosis	Petrovski et al, 2017
c.2628C>G	p.His876Gln	C	aplastic anemia	Du et al, 2008
c.2638G>A	p.Ala880Thr	D	hoyeraal-hreidarsson syndrome	Vogiatzi et al, 2013
c.2638G>A	p.Ala880Thr	D	Pulmonary fibrosis	Borie et al, 2016 Justet et al, 2021
c.2639C>T	p.Ala880Val	D	Pulmonary fibrosis	Borie et al, 2016
c.2648T>G	p.Phe883Cys	D	idiopathic pulmonary fibrosis	Fernandez et al, 2012
c.2665C>T	p.Arg889X	D	aplastic anemia	Calado et al, 2009.1
c.2672T>A	p.Phe883Ile	D	pulmonary fibrosis	Maryoung et al, 2017
c.2678A>T	p.Glu893Val	D	Pulmonary fibrosis	Borie et al, 2016 Justet et al, 2021
c.2701C>T	p.Arg901Trp	D	autosomal recessive dyskeratosis congenita and Hoyeraal Hreidarsson syndrome	Marrone et al, 2007.2
c.2706G>C	p.Lys902Asn	D	autosomal dominant dyskeratosis congenita and aplastic anemia	Armanios et al, 2005
c.2705A>G	p.Lys902Arg	D	aplastic anemia	Parry et al, 2011
c.2747G>A	p.Arg979Gln	E-I	Myelodysplastic syndrome	Schratz et al, 2020
c:2768C>T	p.Pro923Leu	n/a	pulmonary fibrosis	Gansner et al, 2012
c.2775C>A	p.His925Gln	n/a	pulmonary fibrosis	Diaz de Leon et al, 2010
C-terminal	c.2812C>T	p.Arg938Trp	n/a	idiopathic pulmonary fibrosis	Petrovski et al, 2017
	c.2843+1G>A		E-I	Pulmonary fibrosis	Borie et al, 2016 Justet et al, 2021
	c.2849delC	p.Arg951Glyfs*30	E-I	Pulmonary fibrosis	Borie et al, 2016
	c.2851delC	p.Arg951Glyfs*30His	E-I	Pulmonary fibrosis	Justet et al, 2021
	c.2851C>T	p.Arg951Trp	E-I	pulmonary fibrosis/pleuroparenchymal fibroelastosis	Diaz de Leon et al, 2010 Newton et al, 2016 Justet et al, 2021
	c.2869A>C	p.Ser957Arg	E-I	pulmonary fibrosis	Cronkhite et al, 2008
	c.2911C>T	p.Arg971Cys	E-I	Pulmonary fibrosis	Borie et al, 2016 Justet et al, 2021 Borie et al, 2015
	c.2912C>T	p.Arg971His	E-I	dyskeratosis congenita	Carrillo et al, 2012
	c.2915G>A	p.Arg972His	E-I	dyskeratosis congenita	Vulliamy et al, 2011
	c.2935C>T	p.Arg979Trp	E-I	aplastic anemia and dyskeratosis congenita, pulmonary fibrosis	Vulliamy et al, 2005 Xin et al, 2007 Borie et al, 2015 Borie et al, 2016 Justet et al, 2021
	c.2936G>A	p.Arg979Gln	E-I	dyskeratosis congenita	Collopy et al, 2015
	c.2945G>A	p.Cys982Tyr	E-I	Pulmonary fibrosis	Borie et al, 2016
	c.2966T>G	p.Leu989Trp	E-I	Pulmonary fibrosis	Justet et al, 2021
	c.2968C>T	p.Gln990*	E-I	Pulmonary fibrosis	Borie et al, 2016 Justet et al, 2021
	c.2989G>A	p.Val997Met	E-I	Pulmonary fibrosis	Justet et al, 2021
	c.2991delG	p.Val976Valfs	E-I	pulmonary fibrosis	Maryoung et al, 2017
	c.(?)	p.His983Tyr	E-I	Hepatopulmonary syndrome	Gorgy et al, 2015
	c.3007A>G	p.Arg671Trp	E-I	Pulmonary fibrosis	Justet et al, 2021
	c.3014T>C	p.Leu1005Pro	E-I	Pulmonary fibrosis	Justet et al, 2021
	c.3026C>T	p.Ala1009Val	E-I	Pulmonary fibrosis, Myelodysplastic syndrome	Borie et al, 2016 Schratz et al, 2020
	c.3043C>T	p.Cys1015Arg	E-I	aplastic anemia	Du et al, 2009
	c.3055C>T	p.Leu1019Phe	E-I	pulmonary fibrosis/chronic hypersensitivity pneumonitis	Cronkhite et al, 2008 Newton et al, 2016
	c.3073G>T	p.Val1025Phe	n/a	aplastic anemia	Parry et al, 2011
	c.3082A>C	p.Asn1028His	E-II	dyskeratosis congenita	Vulliamy et al, 2011
	c.(?)	p.Phe1032Ile	E-II	idiopathic pulmonary fibrosis	Dai et al, 2014
	c.(?)	p.Thr1039Ala	E-II	bone marrow failure and liver disease	Alder et al, 2018
	c.3148A>G	p.Lys1050Glu	E-III	Pulmonary fibrosis	Cronkhite et al, 2008 Diaz de Leon et al, 2010 Justet et al, 2021
	c.3150G>C	p.Lys1050Asn	E-II	dyskeratosis congenita	Collopy et al, 2015
	c.3184G>A	p.Ala1062Thr	n/a	polymorphism/ acute myeloid leukemia/ aplastic anemia	Du et al, 2009 Alder et al, 2008 Calado et al, 2009 Ziegler et al, 2012
	c.3187G>A	p.Gly1063Ser	n/a	pulmonary fibrosis	Diaz de Leon et al, 2010
	c.3199T>C	p.Ser1067Pro	E-III	Pulmonary fibrosis	Justet et al, 2021
	c.3216G>A	p.Trp1072*	E-III	Pulmonary fibrosis	Borie et al, 2016 Justet et al, 2021
	c.3251 G>C	Arg1084Pro	E-III	pulmonary fibrosis	El-Chemaly et al, 2011
	c.3256C>T	p.Arg1086Cys	E-III	connective tissue disease with usual interstital pneumonia associated	Petrovski et al, 2017
	c.3268G>A	p.Val1090Met	E-III	aplastic anemia	Yamaguchi, 2005
	c.3286C>T	p.Leu1096Phe	E-III	Pulmonary fibrosis	Justet et al, 2021
	c.3323C>T	p.Pro1108Leu	n/a	idiopathic pulmonary fibrosis	Juge et al, 2017
	c.3329C>T	p.Thr1110Met	n/a	idiopathic pulmonary fibrosis	Armanios et al, 2007
	c.3346_3522del177	p.Glu1116fsX	n/a	idiopathic pulmonary fibrosis, fibrosis, and aplastic anemia	Tsakiri et al, 2007
	c.3379T>C	p.Phe1127Leu	n/a	resembles Hoyeraal Hreidarsson syndrome and autosomal recessive dyskeratosis congenita	Vulliamy et al, 2005 Vulliamy et al, 2006
	c.3385A>C	p.Thr1129Pro	n/a	dyskeratosis congenita	Stockklausner et al, 2015
	c.3388A>G	p.Ile1130Val	n/a	aplastic anemia	Vulliamy et al, 2011

DKC1

DKC1 (dyskerin) mutations (X-linked recessive DKC)

Numerous mutations causing amino acid substitutions, deletions, and the loss of the entire exon 15 within dyskerin, a telomerase-associated protein, have been connected with human diseases. Dyskerin associates with the ScaRNA domain of the RNA component of telomerase along with Nop10, Gar1, and NHP2 proteins. In common with RNA pseudouridine synthases, dyskerin contains a TruB domain that participates in eukaryotic ribosomal RNA processing. The TruB domain is composed of two motifs, TruB I and TruB II. In addition to this are two nuclear localization (NL) signals, N-terminal and C-terminal, and the PUA, Pseudouridine synthase and Archaeosine transglycosylase, domain involved in RNA modification.

The above structural organizational scheme for the two domains, TruB and PUA, of the dyskerin protein has indicated the locations of mutations known to cause human diseases. The black line represents the mRNA sequence of 2454 nt with the untranslated regions (UTR) labeled and the grey box corresponds to the protein sequence. The N-terminal and C-terminal nuclear localization (NL) signals are denoted by green, the TruB motifs within the TruB domain by blue, and the PUA domain by orange boxes. The Genbank accession numbers used are NT_011726 for the 14811 bp gene and NM_001363 for the cDNA and amino acid sequences. Below is the 514 amino aid sequence for dyskerin protein with the NL signals, TruB motifs, and PUA domain colored and labeled. The mutated residues are colored red and the change in amino acids is labeled.

514 amino aid sequence for dyskerin protein

Below is a description of the locations within the nucleotide and protein sequence, the amino acid substitutions, the characteristic clinical presentations, and original literature citations that are linked to the published online journal for known mutations within the telomerase-associated protein dyskerin. The cDNA sequence is used for the nucleotide sequence. The mutations are organized by domain from the N-terminus to the C-terminus.

DKC1 mutations

Domains	Mutation	AA substitution	Exon	Presentation	References
UTR	c.-141C>G	n/a	5' UTR	X-linked recessive dyskeratosis congenita	Knight et al, 2001
UTR	c.-142C>G	n/a	5' UTR	X-linked recessive dyskeratosis congenita	Dokal et al, 2000
	c.5C>T	p.Ala2Val	1	X-linked recessive dyskeratosis congenita	Knight et al,1999.1
	c.16+592C>G r.16_17ins247, 16+343_589	p.Val6AlafsX5	IVS1	X-linked recessive dyskeratosis congenita	Knight et al, 2001
	c.29C>T	p.Pro10Leu	2	dyskeratosis congenita and Hoyeraal Hreidarsson syndrome	Vulliamy et al, 2006
	c.85-5C>T	n/a	IVS2	bone marrow failure	Alder et al, 2018
	c.85-5C>G	n/a	IVS2	X-linked recessive dyskeratosis congenita	Knight et al,1999.1
	c.91C>A	p.Gln31Lys	3	X-linked recessive dyskeratosis congenita	Kanegane et al, 2005
	c.91C>G	p.Gln31Glu	3	X-linked recessive dyskeratosis congenita	Wong et al, 2004
	c.(?)	p.Glu35del	3	X-linked recessive dyskeratosis congenita	Xu et al, 2016
	c.106T>G	p.Phe36Val	3	X-linked recessive dyskeratosis congenita	Heiss et al, 1998
	c.109_111delCTT	p.Leu37del	3	X-linked recessive dyskeratosis congenita	Heiss et al, 1998
	c.113T>C	p.Ile38Thr	3	X-linked recessive dyskeratosis congenita and Hoyeraal Hreidarsson syndrome	Cossu et al, 2002
	c.114C>G	p.Ile38Met	3	dyskeratosis congenita	Vulliamy et al, 2011
	c.115A>G	p.Lys39Glu	3	X-linked recessive dyskeratosis congenita	Knight et al,1999.1
	c.119C>G	p.Pro40Arg	3	X-linked recessive dyskeratosis congenita	Heiss et al, 1998
	c.121G>A	p.Glu41Lys	3	X-linked recessive dyskeratosis congenita	Knight et al,1999.1
	c.127A>G	p.Lys43Glu	3	X-linked recessive dyskeratosis congenita	Heiss et al, 2001
	c.145A>T	p.Thr49Ser	3	dyskeratosis congenita	Alder et al, 2013
	c.146C>T	p.Thr49Met	3	X-linked recessive dyskeratosis congenita and Hoyeraal Hreidarsson syndrome	Knight et al,1999.2
	c.(?)	p.Leu54Val	3	X-linked recessive dyskeratosis congenita	Xu et al, 2016
	c.166_167invCT	p.Leu56Ser	3	X-linked recessive dyskeratosis congenita	Kurnikova et al, 2009
	c.194G>A	p.Arg65Lys	4	X-linked recessive dyskeratosis congenita	Hisata et al, 2013
	c.194G>C	p.Arg65Thr	4	X-linked recessive dyskeratosis congenita	Knight et al,1999.1
	c.196A>G	p.Thr66Ala	4	X-linked recessive dyskeratosis congenita, Hoyeraal Hreidarsson syndrome and aplastic anemia	Knight et al,1999.1 Hassock et al, 1999 Keel et al, 2016
	c.200C>T	p.Thr67Ile	4	X-linked recessive dyskeratosis congenita and Hoyeraal Hreidarsson syndrome	Vulliamy et al, 2006
	c.230A>G	p.His68Arg	4	X-linked recessive dyskeratosis congenita	Carrillo et al, 2012
	c.202C>T	p.His68Tyr	4	hoyeraal hreidarrson syndrome	Vulliamy et al, 2011
	c.204C>A	p.His68Gln	4	dyskeratosis congenita and Hoyeraal Hreidarsson syndrome	Vulliamy et al, 2006
	c.214_215CT>TA	p.Leu72Tyr	4	X-linked recessive dyskeratosis congenita	Heiss et al, 1998
	c.227C>T	p.Ser76Leu	4	dyskeratosis congenita	Vulliamy et al, 2011
TruB	c.361A>G	p.Ser121Gly	5	X-linked recessive dyskeratosis congenita and Hoyeraal Hreidarsson syndrome	Knight et al,1999.2
TruB	c.472C>T	p.Arg158Trp	6	X-linked recessive dyskeratosis congenita and Hoyeraal Hreidarsson syndrome	Knight et al, 2001
	c.838A>C	p.Ser280Arg	9	X-linked recessive dyskeratosis congenita	Knight et al, 2001
PUA	c.911G>A	p.Ser304Asn	10	X-linked recessive dyskeratosis congenita, Hoyeraal Hreidarrson syndrome	Du et al, 2009
	c.915+10G>A		10	Myelodysplastic syndrome / Acute myeloid leukemia	Schratz et al, 2021
	c.(?)	p.Ala308Gly	10	bone marrow fialure and primary immunodeficiency	Alder et al, 2018
	c.941A>G	p.Lys314Arg	10	X-linked recessive dyskeratosis congenita and Hoyeraal Hreidarsson syndrome, dyskeratosis congenita	Vulliamy et al, 2006
	c.942G>A	p.Lys314Lys	10	Idiopathic pulmonary fibrosis	Gaysinskaya et al, 2020
	c.949C>G	p.Leu317Val	10	X-linked recessive dyskeratosis congenita	Du et al, 2009
	c.949C>T	p.Leu317Phe	10	X-linked recessive dyskeratosis congenita	Marrone et al, 2003
	c.961C>G	p.Leu321Val	10	X-linked recessive dyskeratosis congenita	Knight et al,1999.1
	c.965G>A	p.Arg322Gln	10	X-linked recessive dyskeratosis congenita	Marrone et al, 2003
	c.1049T>C	p.Met350Thr	11	X-linked recessive dyskeratosis congenita	Knight et al,1999.1
	c.1050G>A	p.Met350Ile	11	X-linked recessive dyskeratosis congenita	Knight et al,1999.1
	c.1058C>T	p.Ala353Val	11	X-linked recessive dyskeratosis congenita, Hoyeraal Hreidarsson syndrome, Myelodysplastic syndrome, Acute myeloid leukemia	Knight et al,1999.1 Schratz et al, 2021
	c.1069A>G	p.Thr357Ala	11	X-linked recessive dyskeratosis congenita	Kanegane et al, 2005
	c.1066T>C	p.Ser356Pro	11	X-linked recessive dyskeratosis congenita	Coelho et al, 2011
	c.1075G>A	p.Asp359Asn	11	dyskeratosis congenita	Vulliamy et al, 2006
	c.1133G>A	p.Arg378Gln	11	Hoyeraal Hreidarrson syndrome	Vulliamy et al, 2011
	c.1150C>T	p.Pro384Ser	11	X-linked recessive dyskeratosis congenita	Marrone et al, 2003
	c.1151C>T	p.Pro384Leu	11	X-linked recessive dyskeratosis congenita	Knight et al, 2001
	c.1156G>A	p.Ala386Thr	12	dyskeratosis congenita and Hoyeraal Hreidarsson syndrome	Vulliamy et al, 2006
	c.1168_1179delAAG	p.Lys390del	12	X-linked recessive dyskeratosis congenita	Carrillo et al, 2012
	c.1193T>C	p.Leu398Pro	12	X-linked recessive dyskeratosis congenita	Hiramatsu et al, 2002
	c.1204G>A	p.Gly402Arg	12	X-linked recessive dyskeratosis congenita	Knight et al,1999.1
	c.1205G>A	p.Gly402Glu	12	X-linked recessive dyskeratosis congenita	Heiss et al, 1998
	c.1213A>G	p.Thr405Ala	12	familial interstitial pneumonia	Kropski et al, 2014
	c.1223C>T	p.Thr408Ile	12	X-linked recessive dyskeratosis congenita	Vulliamy et al, 2006
	c.1226C>T	p.Pro409Leu	12	X-linked recessive dyskeratosis congenita	Ding et al, 2004
	c.1226C>G	p.Pro409Arg	12	dyskeratosis congenita	Alder et al, 2013
	c.1258_1259AG>TA	p.Ser420Tyr	12	dyskeratosis congenita	Vulliamy et al, 2006
	c.1456G>A	p.Gly486Arg	13	hoyeraal-hreidarsson syndrome	Vogiatzi et al, 2013
	c.1477-2A>G	n/a	IVS14	dyskeratosis congenita	Vulliamy et al, 2006
	c.1476+51_oMPP1:c.(?)del	p.Asp493ValfsX12	15	X-linked recessive dyskeratosis congenita	Vulliamy et al, 1999

Nola2

Nola2 (NHP2) mutations (autosomal recessive DKC)

Three point mutations have been discovered within Nola2, the gene that encodes for the protein NHP2, a member of the H/ACA snoRNPs that are involved in various aspects of rRNA processing and modification. NHP2 associates with the ScaRNA domain of the RNA component of telomerase along with dyskerin, Gar1, and Nop10 proteins. These are the first mutations found within NHP2 that is known to cause human disease. The mutation c. 460T>A causes X154R +51aa, the replacement of the stop codon with arginine and the predicted addition of 51 amino acids.

The above structural organizational scheme for the four exons that form the 4498 bp Nola2 gene has indicated the location of mutations known to cause human disease. The black line represents the genomic DNA sequence with the untranslated regions (UTR) labeled. Colored boxes indicate exons 1 though 4. The Genbank accession numbers used are NT_023133 for the genomic DNA sequence and NM_017838 for the cDNA and amino acid sequences. Below is the 153 amino acid sequence for Nhp2 protein with the four exons colored and labeled. The mutated residues are colored red and the change in amino acid is labeled.

153 amino acid sequence for Nhp2 protein

Below is a description of the locations within the nucleotide and protein sequence, the amino acid substitutions, the characteristic clinical presentations, and original literature citations that are linked to the published online journal for known mutation within the telomerase-associated protein NHP2. The cDNA sequence is used for the nucleotide sequence.

Nola2 (NHP2) mutations

Domains	Mutation	AA substitution	Exon	Presentation	References
	c.376G>A	p.Val126Met	4	autosomal recessive dyskeratosis congenita	Vulliamy et al, 2008
	c.415T>C	p.Tyr139His	4	autosomal recessive dyskeratosis congenita	Vulliamy et al, 2008
	c.122G>A	p.Arg41His	1	BMF and PF	Benyelles et al, 2020
	c.182G>C	p.Arg61Pro	2	HH (P1)	Benyelles et al, 2020
	c.259C>T	p.Pro87Ser	3	HH (P1)	Benyelles et al, 2020
	c.289_290del	p.Met97Valfs*2	3	PF	Benyelles et al, 2020
3' UTR	c.460T>A	p.X154Argins51	3' UTR	autosomal recessive dyskeratosis congenita	Vulliamy et al, 2008

Nola3

Nola3 (Nop10) mutations (autosomal recessive DKC)

At present only a single amino acid substitution mutation has been discovered within Nola3, the gene that encodes for the protein Nop10, a member of the H/ACA snoRNPs that are involved in various aspects of rRNA processing and modification. Nop10 associates with the ScaRNA domain of the RNA component of telomerase along with dyskerin, Gar1, and NHP2 proteins. This is the first and only mutation found within Nop10 that is known to cause human disease.

The above structural organizational scheme for the two exons that form the 1446 bp Nola3 gene has indicated the location of the mutation known to cause human disease. The black line represents the genomic DNA sequence with the untranslated regions (UTR) labeled. Colored boxes indicate exons 1 and 2. The Genbank accession numbers used are NT_010194 for the genomic DNA sequence and NM_018648 for the cDNA and amino acid sequences. Below is the 64 amino acid sequence for Nop10 protein with the two exons colored and labeled. The mutated residue is colored red and the change in amino acid is labeled.

64 amino acid sequence for Nop10 protein

Below is a description of the locations within the nucleotide and protein sequence, the amino acid substitutions, the characteristic clinical presentations, and original literature citations that are linked to the published online journal for known mutation within the telomerase-associated protein Nop10. The cDNA sequence is used for the nucleotide sequence.

Nola3 (Nop10) mutations

Domains	Mutation	AA substitution	Exon	Presentation	References
	c.100C>T	p.Arg34Trp	2	autosomal recessive dyskeratosis congenita	Walne et al, 2007
	c.17A>G	p.Tyr6Cys	2	PF	Kannengiesser et al, 2020

WRAP53

WRAP53 (TCAB1) mutations (autosomal recessive DKC)

Currently, four point mutations causing amino acid substitutions have been documented within WRD79, the gene encoding for telomerase Cajal body protein 1 (TCAB1), a protein essential for telomerase localization to Cajal bodies and the biogenesis of the ribonucleoprotein complex. TCAB1 binds to the CAB box motif located within conserved region 7 (CR7) on the telomerase RNA (TR). Loss of function of TCAB1 results in retention of the TR at the nucleoli, inhibiting telomere extension. The mutations within TCAB1 are the first defects associated with telomerase trafficking known to cause human disease.

The above structural organizational scheme of telomerase Cajal body protein 1 contains a Proline rich region and six WD40 motifs (WD1-6) has indicated the locations of mutations known to cause human diseases. The black line represents the mRNA sequence of 1877 nt with the untranslated regions (UTR) labeled and the grey box corresponds to the protein sequence. The Proline rich region is denoted by green and the WD40 motifs by blue boxes. The Genbank accession numbers used are NM_001143992 for the cDNA and amino acid sequences. Below is the 548 amino aid sequence for telomerase Cajal body protein 1 with the Proline rich region and WD40 motifs colored and labeled. The mutated residues are colored red and the change in amino acids is labeled.

548 amino aid sequence for telomerase Cajal body protein 1

Below is a description of the locations within the nucleotide and protein sequence, the amino acid substitutions, the characteristic clinical presentations, and original literature citations that are linked to the published online journal for known mutations within telomerase Cajal body protein 1. The cDNA sequence is used for the nucleotide sequence. The mutations are organized by domain from the N-terminus to the C-terminus.

WRAP53 (TCAB1) mutations

Domains	Mutation	AA substitution	Exon	Presentation	References
	c.(?)	p.Phe164Leu	2	autosomal recessive dyskeratosis congenita	Zhong et al, 2011
WD40	c.1126C>T	p.His376Tyr	7	autosomal recessive dyskeratosis congenita	Zhong et al, 2011
	c.1192C>T	p.Arg398Trp	8	autosomal recessive dyskeratosis congenita	Zhong et al, 2011
	c.(?)	p.Gly435Arg	9	autosomal recessive dyskeratosis congenita	Zhong et al, 2011

PARN

PARN mutations (familial and idiopathic pulmonary fibrosis)

Currently, 29 mutations causing amino acid substitutions, deletions and frame shifts have been documented within PARN, the gene encoding for the poly(A)-specific ribonuclease protein (PARN). The protein is a 3'-enxoribonuclease that degrades poly(A) tails of mRNAs. The mutations in the PARN protein are shown to cause the same genetic diseases as many other telomerase related proteins.

The above structural organizational scheme of poly(A)-specific ribonuclease is organized into two domains, CAF1 and the RNA_bind domain. The black line represents the mRNA sequence of 3083 nt with the untranslated regions (UTR) labeled and the grey box corresponds to the protein sequence. Both the CAF1 domain and the RNA_bind domain are labeled and indicated by solid blue boxes. The Genbank accession numbers used are NM_002582.3 for the cDNA and amino acid sequences. Below is the 639 amino aid sequence for the poly(A)-specific ribonuclease with the CAF1 and RNA_bind domains colored and labeled. The mutated residues are colored red and the change in amino acids is labeled.

639 amino aid sequence for the poly(A)-specific ribonuclease

Below is a description of the locations within the nucleotide and protein sequence, the amino acid substitutions, the characteristic clinical presentations, and original literature citations that are linked to the published online journal for known mutations within the poly(A)-specific ribonuclease protein. The cDNA sequence is used for the nucleotide sequence. The mutations are organized by domain from the N-terminus to the C-terminus.

PARN mutations

Domains	Mutation	AA substitution	Exon	Presentation	References
	NC_000016.9:g.(?_14725823)_(14643928_?)del	Exon 1-21 del		Myelodysplastic syndrome and Acute myeloid leukemia	Schratz et al, 2021 Feurstein et al, 2020
	c.(?_-135_(c.1480+1_1481-1)del	Exon 1-21 del		Myelodysplastic syndrome and Acute myeloid leukemia	Schratz et al, 2021
5' UTR	c.-63C>T	n/a	5' UTR	hoyeraal-hreidarsson syndrome	Burris et al, 2016
CAF1	heterozygous deletion Chr16:14,703,940–14,712,231		6 and 7	Høyeraal-Hreidarsson (P2)	Benyelles et al, 2019
	c.19A>C	p.Asn7His		dyskeratosis congenita and familial pulmonary fibrosis	Moon et al, 2014 Kropski et al, 2017
	c.(?)	p.Phe8LeufsX		idiopathic pulmonary fibrosis	Alder et al, 2018
	c.98C>T	p.Pro33Leu		Pulmonary Fibrosis	Justet et al, 2021
	c.98C>T	p.Gly33Val		Pulmonary Fibrosis	Justet et al, 2021
	c.1251delT	p.Phe418PhefsX6		familial pulmonary fibrosis	Kropski et al, 2017
	c.168G>C	p.Lys56Asn		familial pulmonary fibrosis	Kropski et al, 2017
	c.178-3C>T	n/a	IVS	familial pulmonary fibrosis	Kropski et al, 2017
	c.204G>T	p.Gln68His (homozygous)		Høyeraal-Hreidarsson (P2)	Benyelles et al, 2019
	c.245+75_245+77delCCC	n/a	IVS4	familial pulmonary fibrosis	Kropski et al, 2017
	c.246-2A>G	n/a	IVS4	interstitial pneumonia with autoimmune features and idiopathic pulmonary fibrosis	Newton et al, 2016 Stuart et al, 2015
	c.260C>T	p.Ser87Leu		dyskeratosis congenita	Moon et al, 2014
	c.(?)	p.Phe90Val		idiopahtic pulmonary fibrosis	Alder et al, 2018
	c.529C>T	p.Gln177X		idiopathic pulmonary fibrosis and familial pulmonary fibrosis	Xing et al, 2016 Stuart et al, 2015
	c.543_544insTT	p.Asp182Leufs5		Myelodysplastic syndrome and Acute myeloid leukemia	Schratz et al, 2021
	c.563_564insT	p.Ile188IlefsX7		idiopathic pulmonary fibrosis	Stuart et al, 2015
	c.565G>T	p.Glu189X		familial pulmonary fibrosis	Kropski et al, 2017
	c.602+5G>A	n/a	IVS	familial pulmonary fibrosis	Kropski et al, 2017
	c.659+4_659+7delAGTA	p.208_220del	IVS	dyskeratosis congenita	Tummala et al, 2015
	c.703-11_703-10delAT	n/a	IVS	familial pulmonary fibrosis	Kropski et al, 2017
	c.709C>T	p.Arg237X		hoyeraal-hreidarsson syndrome and non-specific interstital pneumonia	Burris et al, 2016 Petrovski et al, 2017
	c.751delA	p.Arg251GlufsX14		idiopathi pulmonary fibrosis	Stuart et al, 2015
	c.760C>T (heterozygous)	p.Gln254*	E-I	Høyeraal-Hreidarsson (P2)	Benyelles et al, 2019
	c.840+6T>C	n/a	IVS	familial pulmonary fibrosis	Kropski et al, 2017
	c.863dupA	p.Asn288LysfsX23		dyskeratosis congenita	Tummala et al, 2015
	c.887_888delCA	p.Thr296SerfsX14		familial pulmonary fibrosis	Kropski et al, 2017
	c.918+1G>T	p.281_306del	13 skipped	dyskeratosis congenita	Tummala et al, 2015
	c.919_1262del344	p.Asp307ValfsX22	14-18	inherited bone marrow failure	Dhanraj et al, 2015
	c.1006-11G>A	n/a	IVS15	familial pulmonary fibrosis	Kropski et al, 2017
	c.1045C>T	p.Arg349Trp	16	inherited bone marrow failure	Dhanraj et al, 2015
	c.(?) g.14676110C>A	p.Glu374X		idiopathic pulmonary fibrosis	Petrovski et al, 2017
	c.1148C>T	p.Ala383Val		dyskeratosis congenita	Tummala et al, 2015
	c.1214G>C	p.Ser405Thr		Pulmonary Fibrosis	Justet et al, 2021
	c.1262A>G	p.Lys421Arg		idiopathic pulmonary fibrosis	Stuart et al, 2015
RNA_bind	c.(?) g.14647946G>C	p.Leu461Val		idiopathic pulmonary fibrosis	Petrovski et al, 2017
RNA_bind	c.1493G>A	p.Ser498Asn		familial pulmonary fibrosis	Kropski et al, 2017
	c.(?) g.14540858CCT>C	p.Glu585AspfsX5		idiopathic pulmonary fibrosis	Petrovski et al, 2017

TINF2

TINF2 (TIN2) mutations (autosomal dominant DKC)

Currently, three point mutations causing two amino acid substitutions have been documented within TRF1-interacting nuclear factor 2 (TINF2), the gene that encodes for the protein TIN2, a component of the shelterin complex. The shelterin complex is composed of six proteins, three of which that directly associate with the telomeric DNA, TRF1, TRF2, and POT1. Three additional proteins associate with the telomeric DNA binding proteins, TIN2, TPP1, and Rap1. The mutations within TIN2 are the first mutations found within the shelterin complex known to cause human diseases.

The above structural organizational scheme for the nine exons that form the 3032 bp TINF2 gene has indicated the location of mutations known to cause human diseases. The black line represents the genomic DNA sequence with the untranslated regions (UTR) labeled. Colored boxes indicate exons 1-5, 6a, 6c, 6d, and 6e. The Genbank accession numbers used are NT_026437 for the genomic DNA sequence and NM_001099274 for the cDNA and amino acid sequences. Below is the 451 amino acid sequence for TIN2 protein with the nine exons colored and labeled. The mutated residues are colored red and the change in amino acids is labeled above.

451 amino acid sequence for TIN2 protein

Below is a description of the locations within the nucleotide and protein sequence, the amino acid substitutions, the characteristic clinical presentations, and original literature citations that are linked to the published online journal for known mutations within the shelterin protein TIN2. The cDNA sequence is used for the nucleotide sequence. The mutations are organized by domain from the N-terminus to the C-terminus.

TINF2 (TIN2) mutations

Mutation	AA substitution	Exon	Presentation	References
c.640C>T	p.Pro214Ser	6a	bone marrow failure	Vulliamy et al, 2012
c.706C>T	p.Pro236Ser	6a	aplastic anemia	Walne et al, 2008
c.734C>A	p.Ser245Tyr	6a	aplastic anemia	Walne et al, 2008
c.811C>T	p.Gln271X	6a	aplastic anemia	Vulliamy et al, 2011
c.805C>T	p.Gln269X	6a	mucocutaneous features, bone marrow failure, dyskeratosis congenita	Vulliamy et al, 2012 Sasa et al, 2012
c.826delA	p.Arg276GlyfsX41	6a	nail distrophy, bone marrow failure, lichenoid tongue, dry skin, intrauterine frowth retardation	Vulliamy et al, 2012
c.838A>T	p.Lys280X	6a	autosomal-dominant dyskeratosis congenita, Hoyeraal Hreidarsson syndrome, and Revesz syndrome	Walne et al, 2008
c.838A>G	p.Lys280Glu	6a	autosomal-dominant dyskeratosis congenita, Myelodysplastic syndrome and Acute myeloid leukemia	Savage et al, 2008 Schratz et al, 2020
c.839delA	p.Lys280ArgfsX36	6a	dyskeratosis congenita, revesz syndrome	Sasa et al, 2012
c.841G>A	p.Glu281Lys	6a	low wbc	Walne et al, 2008
c.844C>A	p.Arg282Ser	6a	autosomal-dominant dyskeratosis congenita, Revesz syndrome	Savage et al, 2008
c.844C>T	p.Arg282Cys	6a	autosomal-dominant dyskeratosis congenita and aplastic anemia	Walne et al, 2008
c.845G>A	p.Arg282His	6a	autosomal-dominant dyskeratosis congenita, Hoyeraal Hreidarsson syndrome, and Revesz syndrome	Savage et al, 2008
c.847C>T	p.Pro283Ser	6a	autosomal-dominant dyskeratosis congenita and Hoyeraal Hreidarsson syndrome	Walne et al, 2008
c.847C>G	p.Pro283Ala	6a	autosomal-dominant dyskeratosis congenita	Walne et al, 2008
c.848C>A	p.Pro283His	6a	autosomal-dominant dyskeratosis congenita	Walne et al, 2008
c.849delC	p.Thr284GlnfsX33	6a	nail distrophy, bone marrow failure	Vulliamy et al, 2012
c.849_850insC	p.Thr284HisfsX8	6a	autosomal-dominant dyskeratosis congenita and aplastic anemia	Walne et al, 2008
c.850A>G	p.Thr284Ala	6a	autosomal-dominant dyskeratosis congenita	Walne et al, 2008
c.851C>A	p.Thr284Lys	6a	dyskeratosis congenita	Vulliamy et al, 2012
c.851C>G	p.Thr284Arg	6a	bone marrow failure, hair loss, dental loss, pulmonary disease, short stature, osteoporosis	Vulliamy et al, 2012
c.857delTinsGC	p.Met286SerfsX5	6a	nail distrophy, bone marrow failure, microcephaly, low immunoglobulins	Vulliamy et al, 2012
c.860T>C	p.Leu287Pro	6a	autosomal-dominant dyskeratosis congenita	Walne et al, 2008
c.865_866delinsAG	p.Pro289Ser	6a	autosomal-dominant dyskeratosis congenita	Walne et al, 2008
c.867_868insC	p.Phe290LeufsX2	6a	autosomal-dominant dyskeratosis congenita	Walne et al, 2008
c.871A>G	p.Arg291Gly	6a	autosomal-dominant dyskeratosis congenita	Walne et al, 2008
c.892delC	p.Gln298ArgfsX19	6a	autosomal-dominant dyskeratosis congenita	Walne et al, 2008

TPP1

TPP1 mutations

Currently, seven amino acid substitutions and one deletion have been identified in the ACD gene. The ACD gene encodes the protein TPP1, which is a component of the shelterin complex. The shelterin complex consists of six proteins which are encoded by the genes POT1, ACD, TERF1, TERF2, TERF2IP, and TINF2. This complex helps to protect chromosome ends and is necessary for telomere functions.

The above structural organizational scheme for the 12 exons that form the 3304 bp ACD gene has indicated the location of mutations known to cause human diseases. The black line represents the genomic DNA sequence with the untranslated regions (UTR) labeled. Colored boxes indicate exons1-12. The Genbank accession numbers used are NG_042874 for the genomic DNA sequence and NM_001082486 for the cDNA and amino acid sequence. Below is the 544 amino acid sequence for TPP1 protein with the 12 exons colored and labeled. The mutated residues are colored red and the change in amino acids is labeled above.

544 amino acid sequence for TPP1 protein with the 12 exons

Below is a description of the locations within the nucleotide and protein sequence, the amino acid substitions, the characteristic clinical presentations, and original literature citations that are linked to the published online journal for known mutations within the shelterin protein TPP1.The cDNA sequence is used for the nucleotide sequence. The mutations are organized by domain from the N-terminus to the C-terminus.

TPP1 mutations

Mutation	AA substitution	Exon	Presentation	References
c.499_501del	p.Lys170del	3	Aplastic Anemia	Guo et al, 2014
c.499_501del	p.Lys170del	3	Hoyeraal-Hreidarsson syndrome	Kocak et al, 2014
c.598G>A	p.Ala200Thr	4	familial melanoma	Aoude et al, 2014
c.(?)	p.Gly223Val	4	lymphoblastic leukemia (somatic mutation)	Spinella et al, 2015
c.746A>G	p.Asn249Ser	6	familial melanoma	Aoude et al, 2014
c.814G>A	p.Val272Met	7	familial melanoma	Aoude et al, 2014
c.985C>T	p.Gln320X	8	familial melanoma	Aoude et al, 2014
c.964A>T	p.Ile322Phe	8	familial melanoma	Aoude et al, 2014
c.1471C>A	p.Pro491Thr	11	Hoyeraal-Hreidarsson syndrome	Kocak et al, 2014

POT1

POT1 mutations (chronic lymphocytic leukemia)

The protector of telomeres 1 (POT1) protein is a protein in the telombin family is involved in telomere maintenance and protection. The POT1 protein functions as a part of a larger protein complex that binds to TTAGGG telomere repeats in humans. The protein protects telomere DNA from recombination with other DNA, regulates telomere length and contributes to overall chromosome stability.

The above structural organizational scheme for the protection of telomeres 1, transcript variant 1 gene has indicated the location of mutations known to cause human diseases. The black line represents the genomic DNA sequence with the untranslated regions (UTR) labeled. Colored boxes indicate various regions identified within the POT1 protein. The Genbank accession numbers used are NM_015450.2 for the cDNA and amino acid sequences. Below is the 634 amino acid sequence for the POT1 protein with the various protein domains colored and labeled. The mutated residues are colored red and the change in amino acids is labeled above.

634 amino acid sequence for the POT1 protein

Below is a description of the locations within the nucleotide and protein sequence, the amino acid substitutions, the characteristic clinical presentations, and original literature citations that are linked to the published online journal for known mutations within the POT1 protein. Both the cDNA sequence and genomic position are used for the nucleotide sequence. The mutations are organized by domain from the N-terminus to the C-terminus.

POT1 mutations

Domains	Mutation	AA substitution	Exon	Presentation	References
	c.(?) g.124537227T>A	p.Met1Leu	1	chronic lymphocytic leukemia	Ramsay et al, 2012
Telo bind	c.(?)	p.Gln16X	1	chronic lymphocytic leukemia	Herling et al, 2016
	c.(?)	p.Pro34Thr		chronic lymphocytic leukemia	Herling et al, 2016
	c.(?) g.124532338A>T	p.Tyr36Asn	6	chronic lymphocytic leukemia	Ramsay et al, 2012
	c.107A>G	p.Tyr36Cys	6	chronic lymphocytic leukemia	Speedy et al, 2016
	c.(?) g.124511022A>C	p.Tyr66X	7	chronic lymphocytic leukemia	Ramsay et al, 2012
	c.233T>C	p.Ile78Thr		familial melanoma	Wong et al, 2018
	c.266A>G	p.Tyr89Cys		familial melanoma	Robles-Espinoza et al, 2013
	c.(?) g.124503682T>C	p.Lys90Glu	8	chronic lymphocytic leukemia	Ramsay et al, 2012
	c.268A>G	p.Lys90Glu	8	coats plus syndrome	Wilson et al, 2017
	c.(?) g.124503669T>C	p.Gln94Arg	8	chronic lymphocytic leukemia	Ramsay et al, 2012
	c.280C>G	p.Gln94Glu	8	familial melanoma	Robles-Espinoza et al, 2013
	c.(?) g.124503667	p.Gly95Cys		familial glioma	Bainbridge et al, 2015
	c.(?)	p.Ala102Pro		chronic lymphocytic leukemia	Herling et al, 2016
	c.(?) g.124499011C>A	p.Lys103Asn		lymphocytic leukemia	Kim et al, 2016
	c.(?)	p.Ile115PhefxX2		chronic lymphocytic leukemia	Herling et al, 2016
	c.(?) g.124503601G>A	p.Arg117Cys		cardiac angiosarcoma	Calvete et al, 2015
	c.(?) g.124503540C>T	p.Arg137His		familial cutaneous malignant melanoma	Shi et al, 2013
OB2	c.(?)	p.Tyr161Asp		chronic lymphocytic leukemia	Herling et al, 2016
	c.(?) g.124499045T>C	p.Tyr223Cys	9	chrnoic lymphocytic leukemia	Ramsay et al, 2012
	c.(?) g.124499043C>T	p.Asp224Asn		familial cutaneous malignant melanoma	Shi et al, 2013
	c.(?)	p.Leu244Phe		chronic lymphocytic leukemia	Herling et al, 2016
	c.(?) g.124493146G>T	p.Ser250X	10	chronic lymphocytic leukemia	Ramsay et al, 2012
	c.(?) g.124493098t>A	p.His266Leu	10	chronic lymphocytic leukemia	Ramsay et al, 2012
	c.(?)	p.His266Asp/Tyr	10	chronic lymphocytic leukemia	Herling et al, 2016
	c.(?)	p.Gly268Cys	10	chronic lymphocytic leukemia	Herling et al, 2016
	c.(?) g.124493086C>T	p.Ser270Asn	10	familial cutaneous malignant melanoma	Shi et al, 2013
	c.(?) g.124493080C>A	p.Gly272Val	10	chronic lymphocytic leukemia	Ramsay et al, 2012
	c.(?)	p.Arg273Gln	10	chronic lymphocytic leukemia	Herling et al, 2016
	c.818G>T	p.Arg273Leu	10	familial melanoma	Robles-Espinoza et al, 2013
	c.(?)	p.Gly274Arg		chronic lymphocytic leukemia	Herling et al, 2016
	c.965C>T	p.Ser322Leu		coats plus syndrome	Takai et al, 2015
	c.1071_1072insT	p.Gln358SerfsX13		chronic lymphocytic leukemia	Speedy et al, 2016
	c.1127A>G	p.Gln376Arg		chronic lymphocytic leukemia	Speedy et al, 2016
	c.1164-1G>A	n/a	IVS	chronic lymphocytic leukemia	Speedy et al, 2016
	c.(?) g.124481048C>A	p.Glu450X		familial glioma	Bainbridge et al, 2015
	c.(?) g.124469308C>G	p.Ala532Pro		familial cutaneous malignant melanoma	Shi et al, 2013
	c.(?) g.12446532A>C	p.Cys591Trp	18	chronic lymphocytic leukemia	Ramsay et al, 2012
	c.(?) g.124464068TTA>T	p.Asp617GlufsX8		familial glioma	Bainbridge et al, 2015
	c.(?) g.124464052C>G	p.Gln623His		familial cutaneous malignant melanoma	Shi et al, 2013

CTC1

CTC1 mutations

Numerous mutations causing amino acid substitions, deletions, and frame shifts have been found within CTC1,a component of the CST complex. The CST complex, which is composed of the proteins CTC1, STN1, and TEN1, is involved in maintaining telomeres as well as recruiting and activating DNA polα-primase. These are the first mutations found within CTC1 that is known to cause human diseases.

The above structural organizational scheme for the nine exons that form the 23,275 bp CTC1 gene has indicated the location of mutations known to cause human diseases. The black line represents the genomic DNA sequence with the untranslated regions (UTR) labeled. Colored boxes indicate exons 1-23.The Genbank accession numbers used are NG_032148.2 for the genomic DNA sequence and NM_025099.5 for the cDNA and amino acid sequences. Below is the 1217 amino acid sequence for CTC1 protein with 23 exons colored and labeled. The mutated residues are colored red and the change in amino acids is labeled above.

1217 amino acid sequence for CTC1 protein with 23 exons

Below is a description of the locations within the nucleotide adn protein sequence, the amino acid substitions, the characteristic clinical presentations, and original literature citations that are linked to the published online journal for known mutations within the protein CTC1. The cDNA sequence is used for the nucleotide sequence. The mutations are organized by the domain frmo the N-terminus to the C-terminus.

CTC1 mutations

Mutation	AA substitution	Exon	Presentation	References
c.19C>T	p.Gln7*	1	Coats plus	Anderson et al, 2012
c.680C>T	p.Ala227Val	5	cerebroretinal microangiopathy	Polvi, et al, 2012
c.721C>T	p.Gln241*	5	Coats plus	Anderson et al, 2012
c.721C>T	p.Gln241*	5	dyskeratosis congenita	Walne et al, 2013
c.724_727delAAAG	p.Lys242Leufs*41	5	Coats plus	Anderson et al, 2012
c.724_727delAAAG	p.Lys242Leufs*41	5	cerebroretinal microangiopathy	Polvi et al, 2012
c.724_727delAAAG	p.Lys242Leufs*41	5	Dyskeratosis Congenita	Keller et al, 2012
c.724_727delAAAG	p.Lys242Leufs*41	5	dyskeratosis congenita	Walne et al, 2013
c.740T>C	p.Leu247Pro	5	dyskeratosis congenita	Walne et al, 2013
c.775G>A	p.Val259Met	5	Coats plus	Anderson et al, 2012
c.775G>A	p.Val259Met	5	Norrie disease, cerebroretinal microangiopathy	Romaniello et al, 2012
c.833G>T	p.Gly278Val	6	dyskeratosis congenita	Walne et al, 2013
c.833G>T	p.Gly278Val	6	Coats plus	Bisserbe et al, 2015
c.841T>C	p.Tyr281His	6	Coats plus	Bisserbe et al, 2015
c.859C>T	p.Arg287*	6	Coats plus	Anderson et al,2012
c.1058delC	p.Ser353Leufs*14	6	cerebroretinal microangiopathy	Polvi et al., 2012
c.1213delG	p.Asp405MetfsX57	8	Norrie disease, cerebroretinal microangiopathy	Romaniello et al, 2012
c.1270T>G	p.Cys424Gly	8	dyskeratosis congenita	Walne et al, 2013
c.1389_1390insGTTAGGA	p.Leu464Valfs*66	8	dyskeratosis congenita	Walne et al, 2013
c.1451A>C	p.His484Pro	9	Coats plus	Netravathi et al, 2015
c.1507G>C	p.Gly503Arg	9	Coats plus	Anderson et al, 2012
c.1994T>G	p.Val665Gly	12	cerebroretinal microangiopathy	Polvi et al, 2012
c.1994T>G	p.Val665Gly	12	idiopathic portal hypertension	Wartiovaara-Kautto et al, 2016
c.2518C>T	p.Arg840Trp	15	Coats plus	Anderson et al, 2012
c.2611G>A	p.Val871Met	15	Coats plus	Anderson et al, 2012
c.2831delC	p.Pro944Leufs*7	17	cerebroretinal microangiopathy	Polvi et al, 2012
c.2831dupC	p.His945Serfs*56	17	Coats plus	Anderson et al, 2012
c.2923A>G	p.Arg975Gly	17	Coats Plus	Anderson et al, 2012
c.2923A>G	p.Arg975Gly	17	cerebroretinal microangiopathy	Polvi et al, 2012
c.2954_2956delGTT	p.Cys985del	18	Coats plus	Anderson et al, 2012
c.2954_2956delGTT	p.Cys985del	18	cerebroretinal microangiopathy	Polvi et al, 2012
c.2954_2956delGTT	p.Cys985del	18	dyskeratosis congenita	Keller et al, 2012
c.2954_2956delGTT	p.Cys985del	18	dyskeratosis congenita	Walne et al, 2013
c.2959C>T	p.Arg987Trp	18	Coats plus	Anderson et al, 2012
c.2959C>T	p.Arg987Trp	18	dyskeratosis congenita	Walne et al, 2013
c.3019delC	p.Leu1007Cysfs*62	19	cerebroretinal microangiopathy	Polvi et al, 2012
c.3425_3426delTCinsAT	p.Leu1142His	22	cerebroretinal microangiopathy	Polvi et al, 2012
c.3583C>T	p.Arg1195*	23	cerebroretinal microangiopathy	Polvi et al, 2012
c.3586_3606del	p.Leu1196_Arg1202del	23	Coats plus	Anderson et al, 2012
c.3586_3606del	p.Leu1196_Arg1202del	23	cerebroretinal microangiopathy	Polvi et al, 2012

RTEL1

RTEL1 mutations (IPF, DKC and hoyeraal-hreidarsson syndrome)

Numerous mutations causing amino acid substitutions, deletions, and the loss of the entire exon 15 within RTEL1, a telomerase-associated protein, have been connected with human diseases. The RTEL1 protein is a DNA helicase which functions in the protection, stability and elongation of telomeres in humans. RTEL1 interacts with the TRF2, TRF1 and TIN2 proteins in the shelterin complex located at the ends of telomeres to protect telomeres from homologous recombination during DNA replication.

The above schematic shows the larger domains that form the 5042 bp RTEL1 transcript variant 2 gene. The location of some of mutations known to be associated with genetic diseases are shown. Due to the various transcript variants of the RTEL1 gene it is not possible to correctly and accurately show all identified mutations. The black line represents the genomic DNA sequence. Colored boxes indicate translated regions of cDNA and the domains they are located in. The Genbank accession numbers used are NG_033901.1 for the genomic DNA sequence and NM_032957.4 for the cDNA and amino acid sequences. Below is the 1243 amino acid sequence for RTEL1 protein with the various domains colored and labeled. The mutated residues are colored red and the change in amino acids is labeled above.

1243 amino acid sequence for RTEL1 protein

Note: Due to RTEL1 mutations being identified in different isoforms, it is not possible to include all mutations listed below on the same schematic.

Below is a description of the locations within the nucleotide and protein sequence, the amino acid substitutions, the characteristic clinical presentations, and original literature citations that are linked to the published online journal for known mutations within the telomerase-associated protein RTEL1. The cDNA sequence is used for the nucleotide sequence. The mutations are organized by isoform and then by domain from the N-terminus to the C-terminus. Mutations reported without information on the isoform are designated as (?). The NCBI reference sequences used for isoforms 1, 2, and 3 of RTEL1 are, respectively, NP_057518.1, NP_116575.3, and NP_001269938.1.

RTEL1 mutations

Isoform	Mutation	AA substitution	Exon	Presentation	References
1	c.949A>T	p.Lys317X	11	hoyeraal-hreidarsson syndrome	Jullien et al, 2016
	c.(?)	p.Ile398_Lys422del	15 skipped	hoyeraal-hreidarsson syndrome	Jullien et al, 2016
	c.1476G>T	p.Met492Ile	17	hoyeraal-hreidarsson syndrome and myelodysplastic syndrome	Deng et al, 2013 Keel et al, 2016
	c.2920C>T	p.Arg974X	30	hoyeraal-hreidarsson syndrome and familial interstitial pneumonia	Cogan et al, 2015 Deng et al, 2013
2	c.102+2T>C	n/a	IVS	dyskeratosis congenita	Walne et al, 2013
	c.146C>T	p.Thr49Met	3	pulmonary fibrosis	Kannengiesser et al, 2015 Borie et al, 2019
	c.637C>T	p.Arg213Trp	8	pulmonary fibrosis	Kannengiesser et al, 2015 Borie et al, 2019
	c.823G>A	p.Glu275Lys		dyskeratosis congenita	Walne et al, 2013
	.1228_1266+39del78, c.1266+3>G	NA		Pulmonary Fibrosis	Borie et al, 2019
	c.1263+3A>G	p.422_446del	IVS	dyskeratosis congenita	Walne et al, 2013
	c.1548G>T	p.Met516Ile		hoyeraal-hreidarsson syndrome and dyskeratosis congenita	Fedick et al, 2015 Walne et al, 2013
	c.1773G>T	p.Glu615Asp		dyskeratosis congenita and hoyeraal-hreidarsson syndrome	Ballew et al, 2013
	c.1933G>A	p.Ala645Thr	22	dyskeratosis congenita	Ballew et al, 2013
	c.(?) g.62320919A>AC	p.Arg675ThrfsX15		idiopathic pulmonary fibrosis	Petrovski et al, 2017
	c.2044_20 46delCTC	p.Leu682del		Pulmonary Fibrosis	Justet et al, 2021
	c.2097C>G	p.Ile699Met	24	hoyeraal-hreidarsson syndrome	Le Guen et al, 2013
	c.(?) g.623321112G>A	p.Gly703Arg		idiopathic pulmonary fibrosis	Petrovski et al, 2017
	c.2201T>G	p.Leu734Arg		dyskeratosis congenita	Walne et al, 2013
	c.2214-2A>C		IVS	idiopathic pulmonary fibrosis	Petrovski et al, 2017
	c.2233G>A	p.Val745Met	25	hoyeraal-hreidarsson syndrome	Le Guen et al, 2013
	c.2266-1G>C	NA		Pulmonary Fibrosis	Borie et al, 2019
	c.2695T>C	p.Arg213Trp		Pulmonary Fibrosis	Borie et al, 2019 Justet et al, 2021
	c.(?) g.62321477T>C	p.Trp751Arg		idiopathic pulmonary fibrosis	Petrovski et al, 2017
	c.(?) g.62321483C>T	p.Arg753Cys		idiopathic pulmonary fibrosis	Petrovski et al, 2017
	c.2869C>T £	p.Arg957Trp		Pulmonary Fibrosis	Borie et al, 2019
	c.2869C>T	p.Arg957Trp homozygous		Høyeraal-Hreidarsson	Takedachi et al, 2020
	c.2288G>T	p.Gly763Val		hoyeraal-hreidarsson syndrome and dyskeratosis congenita	Fedick et al, 2015 Walne et al, 2013
	c.2896del	p.Glu966Argfs*		Pulmonary Fibrosis	Borie et al, 2019
	c.2761A>G	p.Lys921Glu		dyskeratosis congenita	Walne et al, 2013
	c.2890T>C	p.Phe964Leu	30	pulmonary fibrosis	Kannengiesser et al, 2015 Borie et al, 2019
	c.2903G>A	p.Cys968Tyr		Pulmonary Fibrosis	Justet et al, 2021
	c.2941C>T	p.Arg981Trp		dyskeratosis congenita and hoyeraal-hreidarsson syndrome	Walne et al, 2013 Fedick et al, 2015
	c.2946C>G	p.His982Gln		Pulmonary Fibrosis	Justet et al, 2021
	c.2956C>T	p.Arg986*		Pulmonary Fibrosis	Borie et al, 2019 Justet et al, 2021
	c.2964T>G	p.Phe988Leu		dyskeratosis congenita	Walne et al, 2013
	c.2992C>T	p.Arg998X	30	idiopathic pulmonary fibrosis, dyskeratosis congenita and hoyeraal hreidarsson syndrome	Petrovski et al, 2017 Ballew et al, 2013
	c.(?) g.62324600C>T	p.Arg1010X	30	dyskeratosis congenita, hoyeraal-hreidarsson syndrome and idiopathic pulmonary fibrosis	Petrovski et al, 2017 Ballew et al, 2013
	c.3420C>A	p.Trp1140*		Pulmonary Fibrosis	Borie et al, 2019
	c.3493dupC	p.Gln1165ProfsX22	33	pulmonary fibrosis	Kannengiesser et al, 2015 Justet et al, 2021
	c.3556_3559delAGAC	p.Gln1187Gly fs*176		Pulmonary Fibrosis	Borie et al, 2019
	c.3791G>A	p.Arg1264His		hoyeraal-hreidarsson syndrome, natural killer lymphocyte deficiency, myelodysplastic syndrome, dyskeratosis congenita and familial interstitial pneumonia	Fedick et al, 2015 Hanna et al, 2015 Keel et al, 2016 Walne et al, 2013 Cogan et al, 2015
3	c.602delG	p.Gly201GlufsX15		idiopathic pulmonary fibrosis	Stuart et al, 2015
	c.1135+1G>A			Myelodysplastic syndrome and Acute myeloid leukemia	Schratz et al, 2020
	c.1274T>C	p.Ile425Thr		dyskeratosis congenita	Speckmann et al, 2017
	c.1368G>T	p.Trp456Cys		dyskeratosis congenita	Speckmann et al, 2017
	c.1451C>T	p.Pro484Leu		idiopathic pulmonary fibrosis	Stuart et al, 2015
	c.1760C>T	p.Pro587Leu		Myelodysplastic syndrome and Acute myeloid leukemia	Schratz et al, 2020
	c.1940C>T	p.Pro647Leu		idiopathic pulmonary fibrosis	Stuart et al, 2013
	c.2005C>T	p.Gln693X		idiopathic pulmonary fibrosis	Stuart et al, 2015
	c.2387delT	p.Val796AlafsX4		dyskeratosis congenita	Speckmann et al, 2017
	c.2652+5G>C	p.Pro884_Gln885ins53X13	IVS28	dyskeratosis congenita	Speckmann et al, 2017
	c.2869C>T	p.Arg957Trp		hoyeraal-hreidarsson syndrome	Touzot et al, 2016
	c.2892T>G	p.Phe964Leu	30	hoyeraal-hreidarsson syndrome	Touzot et al, 2016
	c.3371A>C	p.His1124Pro		idiopahtic pulmonary fibrosis	Stuart et al, 2015
	c.3730T>C	p.Cys1244Arg	34B	hoyeraal-hreidarsson syndrome	Le Guen et al, 2013
	c.3730delTG	p.Cys1244ProfsX17		dyskeratosis congenita	Speckmann et al, 2017
	c.3802T>C	p.Cys1268Arg		hoyeraal-hreidarsson syndrome	Touzot et al, 2016
	c.3880G>T	p.Val1294Phe		hoyeraal-hreidarsson syndrome	Touzot et al, 2016
(?)	c.102+1G>A	n/a	IVS	cryptic dyskeratosis congenita	Yamaguchi et al, 2015
	c.(?)	p.Thr56Met		myelodysplastic syndrome	Keel et al, 2016
	c.(?)	p.His116Arg		myelodysplastic syndrome	Keel et al, 2016
	c.958+1G>GT	n/a	IVS10	familial interstitial pneumonia	Cogan et al, 2015
	c.1482-1G>A	n/a	IVS	afmilial interstitial pneumonia	Cogan et al, 2015
	c.1618T>G	p.Ser540Ala		familial interstitial pneumonia	Cogan et al, 2015
	c.(?)	p.Gln669X		chronic hypersensitivity pneumonitis	Newton et al, 2016
	c.(?)	p.Phe709Leu		cryptic dyskeratosis congenita	Yamaguchi et al, 2015
	c.2219_2227del	p.740_742del		familial interstitial pneumonia	Cogan et al, 2015
	c.2413+1G>C	n/a	IVS25	familial interstitial pneumonia	Cogan et al, 2015
	c.2695T>C	p.Phe899Leu		idiopathic pulmonary fibrosis	Juge et al, 2017
	c.2824G>A	p.Asp942Asn		idiopathic pulmonary fibrosis	Juge et al, 2017
	c.2875C>T	p.His959Tyr		idiopathic pulmonary fibrosis	Juge et al, 2017
	c.2956C>T	p.Arg986X		hoyeraal-hreidarsson syndrome	Moriya et al, 2016
	c.2957G>A	p.Arg986Gln		familial interstitial pneumonia	Cogan et al, 2015
	c.3126A>C	p.Gln1024His		hoyeraal-hreidarsson syndrome	Mariya et al, 2016

NAF1

NAF1 mutations

Currently, there are two frame shift mutataions that have been identified in the NAF1 protein. NAF1 is part of an H/ACA motif-binding complex, which consists of the proteins dyskerin, NHP2, NOP10, and NAF1. The assembly of this complex with hTR transcript begins the biogenisis of the human telomerase holoenzyme.

The above structural organizational scheme for the eight exons that form the NAF1 gene has indicated the location of mutations known to cause human diseases. The black line represents the genomic DNA sequence with the untranslated regions (UTR) labeled. Colored boxes indicate exons 1-8. The Genbank accession number used was NM_138386.2 for the cDNA and amino acid sequences. Below is the 494 amino acid sequence for the NAF1 protein with the 8 exons numbered and labeled. The mutated residues are colored red and the change in amino acids is labeled above.

494 amino acid sequence for the NAF1 protein with the 8 exons

Below is a description of the locations within the nucleotide and protein sequence, the amino acid substitutions, the characteristic clinical presentations, and original literature citations that are linked to the published online journal for known mutations within the NAF1 protein. Both the cDNA sequence and genomic position are used for the nucleotide sequence. The mutations are organized by domain from the N-terminus to the C-terminus.

NAF1 mutations

Mutation	AA substitution	Exon	Presentation	References
c.956_957delAA	p.Lys319Argfs*21	7	Idiopathic Pulonary Fibrosis	Stanley et al, 2016
c.984insA	p.Ser329Ilefs*12	7	Pulmonary Fibrosis-Emphysema	Stanley et al, 2016
c.950A>T	p.Asp317Val	7	Myelodysplastic syndrome / Acute myeloid leukemia	Schratz et al, 2021

ZCCHC8

ZCCHC8 mutations

Currently, there is one substitution mutataion that has been identified in the ZCCHC8 protein. ZCCHC8 is a component of the nuclear exosome targeting complex (NEXT), involved in the processing of intronless RNAs, such as telomerase RNA, a special class of replication dependent histones, and RNAs that encode cilia protein components.

The above structural organizational scheme for the fourteen exons that form the ZCCHC8 gene have indicated the location of the mutation known to cause human disease. The black line represents the genomic DNA sequence with the untranslated regions (UTR) labeled. Colored boxes indicate amino acid coding sequences 1-14. The Genbank accession number used was NM_017612.5 for the cDNA and amino acid sequences. Below is the 707 amino acid sequence for the ZCCHC8 protein with the 14 exons numbered and labeled. The mutated residues are colored red and the change in amino acids is labeled above.

707 amino acid sequence for the ZCCHC8 protein with the 14 exons

Below is a description of the locations within the nucleotide and protein sequence, the amino acid substitutions, the characteristic clinical presentations, and original literature citations that are linked to the published online journal for known mutations within the ZCCHC8 protein. Both the cDNA sequence and genomic position are used for the nucleotide sequence. The mutations are organized by domain from the N-terminus to the C-terminus.

ZCCHC8 mutations

Domains	Mutation	AA substitution	Exon	Presentation	References
	c.C557T	p.Pro186Leu	6	Familial Idiopathic Pulmonary Fibrosis	Gable et al, 2019

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