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 for telomerase RNA and protein components 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
5' UTR c.-99C>G 5' UTR paroxysmal nocturnal hemoglobinuria, menorrhagia, anemia, and thrombocytopenia
Pseudoknot r.2g>c 5' end aplastic anemia Marrone et al, 2007.1
r.28_34del7 P1a aplastic anemia Xin et al, 2007
r.35c>u P1b hypoplastic myelodysplastic syndrome Du et al, 2009
r.37a>g P1b autosomal dominant dyskeratosis congenita, idiopathic pulmonary fibrosis, and dyspnea
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.58g>a template flanking polymorphism
r.72c>g P2a.1 aplastic anemia Vulliamy et al, 2002
r.79delc P2a aplastic anemia Vulliamy et al, 2006
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.107_108gc>ag P3 autosomal dominant dyskeratosis congenita Vulliamy et al, 2001
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.143g>a P2a.1 autosomal dominant dyskeratosis congenita and aplastic anemia
Parry 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.204c>g P1a aplastic anemia Fogarty et al, 2003
Hypervariable r.216_229del14 P4.1 autosomal dominant dyskeratosis congenita Ly et al, 2005.2
r.228g>a P4.1 polymorphism
CR4-CR5 r.305g>a P6.1 aplastic anemia Yamaguchi et al, 2003
r.316_451del136 J6/5 to Box ACA autosomal dominant dyskeratosis congenita Vulliamy et al, 2004
r.322g>a P5 myelodysplasia and refractory anemia Yamaguchi et al, 2003
  r.325g>u P5 idiopathic pulmonary fibrosis Alder et al, 2008
ScaRNA 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.450g>a Box ACA aplastic anemia Yamaguchi et al, 2003
3' UTR c.467T>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.97C>T p.Pro33Ser n/a idiopathic pulmonary fibrosis and fibrosis Tsakiri et al, 2007
c.164T>A p.Leu55Gln n/a idiopathic pulmonary fibrosis Armanios et al, 2007
  p.Pro65Ala GQ   Calado et al, 2009
c.277+1G>A n/a IVS1 idiopathic pulmonary fibrosis Armanios et al, 2007
c.(334_336)delC p.Pro112ProfsX16 GQ idiopathic pulmonary fibrosis Armanios et al, 2007
c.430G>A p.Val144Met GQ idiopathic pulmonary fibrosis Tsakiri et al, 2007
  p.Val170Met GQ aplastic anemia and pulmonary fibrosis Parry et al, 2011
c.604G>A p.Ala202Thr n/a aplastic anemia
c.1849C>T p.Ala279Thr n/a polymorphism
  p.Val299Met n/a   Calado et al, 2009
c.1234C>T p.His412Tyr CP polymorphism
c.1321_1323delGAG p.Glu441del n/a polymorphism Yamaguchi et al, 2005
c.1456C>T p.Arg486Cys QFP idiopathic pulmonary fibrosis Tsakiri et al, 2007
  Arg522Lys n/a   Calado et al, 2009
c.1710G>(T_C) p.Lys570Asn T aplastic anemia Xin et al, 2007
Reverse transcriptase   p.Arg631Gln 2   Diaz de Leon et al, 2010
  p.Arg671Trp 3b   Diaz de Leon et al, 2010
c.2045G>A p.Gly682Asp 3b aplastic anemia Liang et al, 2006
c.2080G>A p.Val694Met 3c aplastic anemia Yamaguchi 2005
  p.Pro702Leu n/a   Cronkhite et al, 2008
c.2110C>T p.Pro704Ser n/a autosomal dominant dyskeratosis congenita and aplastic anemia
c.2147C>T p.Ala716Val A severe pancytopenia and aplastic anemia Du et al, 2009
  p.Ala716Thr A aplastic anemia Parry et al, 2011
c.2162C>G p.Pro721Arg n/a autosomal recessive dyskeratosis congenita Vulliamy et al, 2006
c.2177C>T p.Thr726Met IFDa aplastic anemia Liang et al, 2006
c.2240delT p.Val747AlafsX20 IFDb idiopathic pulmonary fibrosis Tsakiri et al, 2007
c.2315A>G p.Tyr772Cys IFDb aplastic anemia Yamaguchi 2005
c.2431C>T p.Arg811Cys IFDc autosomal recessive dyskeratosis congenita Marrone et al, 2007.2
  p.Leu841Phe B pulmonary fibrosis Parry et al, 2011
c.2537A>G p.Tyr846Cys B aplastic anemia Du et al, 2008
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
  p.Val867Met C   Diaz de Leon et al, 2010
c.2628C>G p.His876Gln C aplastic anemia Du et al, 2008
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
  p.Lys902Arg D aplastic anemia Parry et al, 2011
  p.His925Gln n/a   Diaz de Leon et al, 2010
C-terminal   p.Arg951Trp E-I   Diaz de Leon et al, 2010
  p.Ser957Arg E-I   Cronkhite et al, 2008
c.2935C>T p.Arg979Trp E-I aplastic anemia and dyskeratosis congenita
c.3043C>T p.Cys1015Arg E-I aplastic anemia Du et al, 2009
  p.Leu1019Phe E-I   Cronkhite et al, 2008
  p.Lys1050Glu E-II   Cronkhite et al, 2008
c.3184G>A p.Ala1062Thr n/a polymorphism
  p.Gly1063Ser n/a   Diaz de Leon et al, 2010
c.3268G>A p.Val1090Met E-III aplastic anemia Yamaguchi 2005
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
  p.Val1025Phe n/a aplastic anemia Parry et al, 2011
c.3379T>C p.Phe1127Leu n/a resembles Hoyeraal Hreidarsson syndrome and autosomal recessive dyskeratosis congenita

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
URR c.-141C>G n/a 5' URR X-linked recessive dyskeratosis congenita Knight et al, 2001
c.-142C>G n/a 5' URR 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>G p.(?) IVS2 X-linked recessive dyskeratosis congenita Knight et al,1999.1
  c.91C>G p.Gln31Glu 3 X-linked recessive dyskeratosis congenita Wong et al, 2004
  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.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.146C>T p.Thr49Met 3 X-linked recessive dyskeratosis congenita and Hoyeraal Hreidarsson syndrome
  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 and HH
  c.200C>T p.Thr67Ile 4 X-linked recessive dyskeratosis congenita and Hoyeraal Hreidarsson syndrome Vulliamy et al, 2006
  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
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.941A>G p.Lys314Arg 10 X-linked recessive dyskeratosis congenita and Hoyeraal Hreidarsson syndrome, dyskeratosis congenita Vulliamy et al, 2006
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 and Hoyeraal Hreidarsson syndrome Knight et al,1999.1
c.1075G>A p.Asp359Asn 11 dyskeratosis congenita Vulliamy et al, 2006
  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.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.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.1258_1259AG>TA p.Ser420Tyr 12 dyskeratosis congenita Vulliamy et al, 2006
  c.1477-2A>G p.(?) 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
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

WRD79 (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

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.706C>T p.Pro236Ser 6a aplastic anemia Walne et al, 2008
  c.734C>A p.Ser245Tyr 6a aplastic anemia Walne et al, 2008
  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 Savage et al, 2008
  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.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.860T>C p.Leu287Pro 6a autosomal-dominant dyskeratosis congenita Walne et al, 2008
  c.865_866indelsAG 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