Site Updated: October 2021
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Disease background

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 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.


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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.
Domains Mutation Region Presentation References
Promoter
c.1-22C>U Pulmonary Fibrosis
c.-771A>G n/a myelodysplastic syndrome
c.-714insC  n/a myelodysplastic sydrome
c.-240delCT n/a myelodysplastic syndrome Field et al, 2006
c.-99C>G n/a paroxysmal nocturnal hemoglobinuria, menorrhagia, anemia, and thrombocytopenia
Pseudoknot
r.1-22C>U Pulmonary Fibrosis
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
r.28_34del7 P1a aplastic anemia Xin et al, 2007
r.30G>A Pulmonary Fibrosis
r.35C>U NA Pulmonary Fibrosis
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
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
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
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
r.93g>c P2b dyskeratosis congenita
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
r. 109_123del15 P3_P2b pancytopenia Calado et al, 2009.2
r.110_113delGACU Pulmonary Fibrosis
r.110_113delgacu P3 aplastic anemia, myelodysplasia and leukemia
r.116c>u P2b aplastic anemia and thrombocytopenia
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
r.135G>C Pulmonary Fibrosis
r.143g>a P2a.1 autosomal dominant dyskeratosis congenita and aplastic anemia
r.164A>C NA Pulmonary Fibrosis
r.170C>A NA Pulmonary Fibrosis
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
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
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
r.235C>G Pulmonary Fibrosis
r.236C>U Pulmonary Fibrosis
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
  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
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)
r.448A>G Pulmonary Fibrosis
r.448a>g Box ACA dyskeratosis congenita
3' UTR c.467u>c 3' UTR aplastic anemia Yamaguchi et al, 2003

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.


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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.


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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.
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
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
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
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
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
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
c.1589C>T p.Pro530Leu n/a hoyeraal-hreidarsson syndrome/dyskeratosis congenita/hepatic cirrhosis/pulmonary fibrosis
c.1604G>A p.Arg535His n/a Myelodysplastic syndrome Schratz et al, 2020
c.1630T>C p.Phe544Leu T Pulmonary fibrosis
c.1692G>A p.Thr564Thr T Pulmonary fibrosis Borie et al , 2016
c.1698_1700delCAC p.Thr567del T Pulmonary fibrosis
c.1710G>C p.Lys570Asn T Pulmonary fibrosis
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
c.1864C>T p.Arg622Cys 1 Pulmonary fibrosis
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
c.2011C>T p.Arg671Trp 3b Pulmonary fibrosis
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
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
c.2113G>C p.Glu705Gln n/a dyskeratosis congenita Collopy et al, 2015
c.2146G>A p.Ala716Thr A Aplastic anemia, pulmonary fibrosis
c.2147C>T p.Ala716Val A severe pancytopenia and aplastic anemia Du et al, 2009
c.2147C>T p.Ala716Val A Pulmonary fibrosis
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
c.2240delT p.Val747AlafsX20 IFDb idiopathic pulmonary fibrosis Tsakiri et al, 2007
c.2267G>T p.Arg756Leu IFDb Pulmonary fibrosis
c.2287-2A>G IFDb Pulmonary fibrosis
c.2287-2A>C p.Arg756Leu n/a Pulmonary fibrosis
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
c.2354C>T p.Pro785Leu IFDb acute myeloid leukaemia
c.2377G>A p.Glu793Lys IFDb Pulmonary fibrosis Justet et al, 2021
c.2383-2A>G n/a IVS idiopathic pulmonary fibrosis
c.2431C>T p.Arg811Cys IFDc autosomal recessive dyskeratosis congenita Marrone et al, 2007.2
c.2431C>T p.Arg811Cys IFDc Pulmonary fibrosis
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
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
c.(?) p.Arg865Ala C idiopathic pulmonary fibrosis
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
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
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
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
c.2869A>C p.Ser957Arg E-I pulmonary fibrosis Cronkhite et al, 2008
c.2911C>T p.Arg971Cys E-I Pulmonary fibrosis
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
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
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
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
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
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
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
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
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 (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.


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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.

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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.
Domains Mutation AA substitution Exon Presentation References
UTR c.-141C>G n/a 5' UTR X-linked recessive dyskeratosis congenita Knight et al, 2001
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
  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
  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
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
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
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
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
  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 (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.


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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.


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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.
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 (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.


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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.


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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.
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 (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.


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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.


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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.
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 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.


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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.


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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.
Domains
Mutation
AA substitution
Exon
Presentation
References
NC_000016.9:g.(?_14725823)_(14643928_?)del Exon 1-21 del Myelodysplastic syndrome and Acute myeloid leukemia
c.(?_-135_(c.1480+1_1481-1)del Exon 1-21 del Myelodysplastic syndrome and Acute myeloid leukemia
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
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
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
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
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
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 (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.


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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.


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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.
Domains
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
  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
  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 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.


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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.

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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.
Domains
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 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.


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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.


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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.

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 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.

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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.

download formats: .pdf and .jpg

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.
Domains
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 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.


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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.

download: .jpg


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.

Domains
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
  c.2920C>T p.Arg974X 30 hoyeraal-hreidarsson syndrome and familial interstitial pneumonia
2 c.102+2T>C n/a IVS dyskeratosis congenita Walne et al, 2013
  c.146C>T p.Thr49Met 3 pulmonary fibrosis
  c.637C>T p.Arg213Trp 8 pulmonary fibrosis
  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
  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
  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
  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
  c.2903G>A p.Cys968Tyr Pulmonary Fibrosis Justet et al, 2021
  c.2941C>T p.Arg981Trp   dyskeratosis congenita and hoyeraal-hreidarsson syndrome
  c.2946C>G p.His982Gln Pulmonary Fibrosis Justet et al, 2021
  c.2956C>T p.Arg986* Pulmonary Fibrosis
  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
  c.(?) g.62324600C>T p.Arg1010X 30 dyskeratosis congenita, hoyeraal-hreidarsson syndrome and idiopathic pulmonary fibrosis
  c.3420C>A p.Trp1140* Pulmonary Fibrosis Borie et al, 2019
  c.3493dupC p.Gln1165ProfsX22 33 pulmonary fibrosis
  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
  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 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.

download formats: .pdf and .jpg

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.

download formats: .pdf and .jpg

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.
Domains
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 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.

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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.

download formats: .pdf and .jpg

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