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.

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

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

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

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

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.

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

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

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.

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

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

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.

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

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

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.

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

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

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.

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

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

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.

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

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

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.

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

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

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.

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

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

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.

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

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

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.

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

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

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.

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

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

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.