Alternative titles; symbols
HGNC Approved Gene Symbol: DKC1
SNOMEDCT: 708536001;
Cytogenetic location: Xq28 Genomic coordinates (GRCh38) : X:154,762,864-154,777,689 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xq28 | ?Cataracts, hearing impairment, nephrotic syndrome, and enterocolitis 1 | 301108 | X-linked dominant | 3 |
| Dyskeratosis congenita, X-linked | 305000 | X-linked recessive | 3 |
Dyskerin is a nucleolar protein present in small nucleolar ribonucleoprotein particles that modify specific uridine residues of ribosomal RNA by converting them to pseudouridine. Dyskerin is also a component of the telomerase complex (summary by Mochizuki et al., 2004).
By positional cloning, Heiss et al. (1998) identified a gene, symbolized DKC1, in the Xq28 region that is the cause of X-linked recessive dyskeratosis congenita (DKCX; 305000). Heiss et al. (1998) found that the DKC1 gene is highly conserved across species barriers and is the ortholog of rat Nap57 and S. cerevisiae Cbf5. The gene product, referred to as dyskerin, contains 2 TruB pseudouridine synthase motifs, multiple phosphorylation sites, and a carboxy-terminal lysine-rich domain. By analogy to the function of known dyskerin orthologs, Heiss et al. (1998) predicted that dyskerin is involved in the cell cycle and nucleolar function.
Hassock et al. (1999) determined that the DKC1 gene comprises 15 exons spanning at least 16 kb and is transcribed into a widely expressed 2.6-kb message. The single-copy DKC1 gene is transcribed from a CpG island 60 kb centromeric to the factor VIII gene (F8; 300841) in distal Xq28 and lies tail to tail with the palmitoylated erythrocyte membrane protein-1 gene (MPP1; 305360).
Hassock et al. (1999) determined that the DKC1 gene maps to chromosome Xq28, centromeric to the factor VIII gene (F8; 300841).
McGrath (1999) commented on the function of dyskerin in relation to its widespread tissue distribution, the array of clinical features in DKC, and the need to explain the cause of the dysplasia and the bone marrow abnormalities in this disorder. Sequence homology assessment predicted that dyskerin is a nuclear protein that is responsible for some early steps in ribosomal RNA processing, although it was not clear whether dyskerin mutations slow ribosome synthesis or make ribosomes functionally abnormal (Heiss et al., 1998; Luzzatto and Karadimitris, 1998). The ubiquitous distribution of dyskerin suggested to McGrath (1999) that there may be functional redundancy in some tissues, but that its function may be more critical in cells with a high turnover, such as keratinocytes, mucosal epithelium, and bone marrow. Perhaps in these tissues the risk of development of malignant tumors reflects the consequences of defective translation brought about through mutated dyskerin. Dyskerin also seems to be a centromere or microtubule protein and, if mutated, may give rise to abnormalities with chromosome segregation and consequent malignant predisposition.
Mitchell et al. (1999) demonstrated that dyskerin is associated not only with H/ACA small nucleolar RNAs but also with human telomerase RNA (TERC; 602322), which contains an H/ACA RNA motif. Telomerase adds simple sequence repeats to chromosome ends using an internal region of its RNA as a template and is required for the proliferation of primary human cells. Mitchell et al. (1999) found that primary fibroblasts and lymphoblasts from DKC-affected males were not detectably deficient in conventional H/ACA small nucleolar RNA accumulation or function. However, DKC cells had a lower level of telomerase RNA, produced lower levels of telomerase activity than matched normal cells, and had shorter telomeres. Mitchell et al. (1999) concluded that the pathology of DKC is consistent with compromised telomerase function leading to a defect in telomere maintenance, which may limit the proliferative capacity of human somatic cells in epithelia and blood.
Using immunoprecipitation studies and Western blot analysis, Pogacic et al. (2000) found that NOP10 (NOLA3; 606471) associates with NHP2 (NOLA2; 606470), dyskerin, and GAR1 (NOLA1; 606468) in structures corresponding to H/ACA small nucleolar RNPs (snoRNPs), but not to C/D snoRNPs, and to telomerase. SnoRNPs of the H/ACA class specify the sites of uridine-to-pseudouridine conversion. Immunofluorescence microscopy demonstrated colocalization of NOLA3 with NOLA1, NOLA2, and DKC1, but not with fibrillarin (FBL; 134795), in nucleolar dense fibrillar components and in Cajal bodies (also called coiled bodies; see 600272).
The protein dyskerin is a component of the box H/ACA small nucleolar RNAs (snoRNAs) and is also functionally associated with the RNA component of TERC. Most mutations causing dyskeratosis congenita are missense mutations, although noncoding mutations have been described. One of these is a point mutation (-141C-G; 300126.0008) in a putative Sp1 binding site in the 5-prime upstream region of the DKC1 gene, which presumably represents the promoter region of the gene. Salowsky et al. (2002) compared the promoter sequences of both the human and mouse genes and provided a functional characterization of the human DKC1 promoter that included a characterization of the disease-associated implications caused by the -141C-G mutation. By reporter gene analysis, functional regions of the DKC1 promoter were delineated. The core promoter region critical for basal level of transcription was found to lie at -10 to -180. Bandshift and supershift experiments clearly demonstrated a mutual binding of transcription factors Sp1 and Sp3 to 2 of 5 putative GC box/Sp1 binding sites located in the core promoter region. An additional GC box interacts only with the Sp1 transcription factor. Salowsky et al. (2002) provided evidence that the mentioned DKC1 mutation in one of the Sp1 binding sites results in reduced promoter activity.
Montanaro et al. (2002) observed that in lymphoblastoid cell lines from patients with dyskeratosis congenita, rRNA transcription and maturation and proliferative capability remained unimpaired. Increasing the number of cell cycles led to a steep rise in the apoptotic fraction of dyskeratosis congenita cells. These findings demonstrated that whereas dyskeratosis congenita cell lines do not display proliferation defects, they do show progressively increasing levels of apoptosis in relation to the number of cell divisions. This observation is consistent with the delayed onset of dyskeratosis congenita proliferating-tissue defects, which do not emerge during embryonal development as would be expected with ribosomal biogenesis alterations, and with the increasing severity of the proliferating-tissue defects over time.
Wong and Collins (2006) found that primary dermal fibroblasts cultured from a DKC patient underwent premature senescence, consistent with the presence of short telomeres, compared with dermal fibroblasts cultured from his asymptomatic maternal grandmother. Expression of exogenous TERT (187270) from a retroviral vector increased telomerase activity in DKC patient cells, resulting in increased steady-state levels of TERC and elimination of premature senescence, but did not confer telomere length maintenance. DKC patient cells expressing both TERT and TERC from a single retroviral vector gained and maintained long telomeres. Following rescue from premature senescence, DKC patient cells from 2 different families had normal levels of rRNA pseudouridine modification and no dramatic delay in rRNA precursor processing, in contrast with phenotypes reported for mouse models of DKC. Wong and Collins (2006) concluded that defects in DKC patient cells arise solely from reduced accumulation of TERC.
Cohen et al. (2007) purified human telomerase 10(8)-fold, with the final elution dependent on the enzyme's ability to catalyze nucleotide addition onto a DNA oligonucleotide of telomeric sequence, thereby providing specificity for catalytically active telomerase. Mass spectrometric sequencing of the protein components and molecular size determination indicated an enzyme composition of 2 molecules each of TERT, TERC, and dyskerin.
Machado-Pinilla et al. (2008) showed that expression of GSE24-2, a genetic suppressor element coding for the pseudouridine synthase domain of DKC1, increased survival against cisplatin and telomerase inhibitors in human cells. GSE24-2 activated the MYC (190080) promoter through nuclease hypersensitive element III (NHEIII) and, consequently, activated the TERT promoter. Expression of GSE24-2 was associated with increased telomerase activity in a human lung fibroblast cell line and in cells from patients with X-linked DKC. Furthermore, expression of GSE24-2 rescued X-linked DKC cells from premature senescence.
Venteicher et al. (2009) showed that TCAB1 (612661) associates with active telomerase enzyme (TERT; 187270), established telomerase components including dyskerin and TERC (602322), and small Cajal body RNAs (scaRNAs), which are involved in modifying splicing RNAs. Depletion of TCAB1 by using RNA interference prevented TERC from associating with Cajal bodies, disrupted telomerase-telomere association, and abrogated telomere synthesis in telomerase. Thus, Venteicher et al. (2009) concluded that TCAB1 controls telomerase trafficking and is required for telomere synthesis in human cancer cells.
Grozdanov et al. (2009) stated that NAP57 together with NOP10 and NHP2 forms a core trimer that is essential for the stability of all H/ACA RNPs. A fourth H/ACA core protein GAR1 interacts with NAP57 independently. They previously found that H/ACA RNP assembly factor SHQ1 (613663) binds to NAP57. Protein interaction assays using NAP57 deletion constructs showed that the N terminus (NT) and C terminus (CT) of NAP57 together formed the binding surface for SHQ1. By 3-dimensional modeling, Grozdanov et al. (2009) showed that the NT folded around the CT and that the domain did contact any other proteins of the particle or the H/ACA RNA. DKC mutations are concentrated in the NT and CT but not in the central catalytic domain of NAP57. The authors showed that various mutations (see, e.g., 300126.0006 and 300126.0010) resulted in increased or decreased binding affinity for SHQ1, thus reducing NAP57 availability for RNP assembly.
Rashid et al. (2006) determined the crystal structure of the Pyrococcus furiosus dyskerin homolog, Cbf5, in complex with Nop10 (NOLA3; 606471) and Gar1 (NOLA1; 606468) to 2.1-angstrom resolution. Based on the Cbf5 crystal structure and sequence alignment of Cbf5 with human dyskerin, Rashid et al. (2006) determined that most dyskeratosis-causing mutations colocalize on 1 side of the pseudouridine synthase and Archaeosine transglycosylase (PUA) domain of dyskerin, which is predicted to play a specific role in binding H/ACA and telomerase RNAs. Rashid et al. (2006) suggested that mutations within the PUA domain may weaken interactions between dyskerin and its cognate RNAs, leading to decreased cellular accumulation of the RNAs. Alternatively, the mutations may affect a binding site of an unidentified factor.
Dyskeratosis Congenita, X-Linked
In patients with X-linked dyskeratosis congenita (DKCX; 305000), Heiss et al. (1998) identified missense mutations in the DKC1 gene (300126.0001-300126.0005).
Knight et al. (1999) detected mutations in the DKC1 gene in 21 of 37 families with dyskeratosis congenita. These mutations consisted of 11 different single-nucleotide substitutions, which resulted in 10 missense mutations and 1 putative splicing mutation within an intron. The missense change A353V (300126.0006) was observed in 11 different families and was shown to be a recurring de novo event. Two polymorphisms were also detected, 1 of which resulted in the insertion of an additional lysine in the C-terminal polylysine domain. It is striking that X-linked dyskeratosis congenita is predominantly caused by missense mutations.
Knight et al. (2001) screened male patients with dyskeratosis congenita from 25 families for mutations in the DKC1 gene. Sequence variations were detected in 10 of the families. In 5 families, previously identified mutations were detected. Of the 5 novel sequence changes, 3 were coding changes. A fourth sequence change was detected in the 5-prime flanking region that disrupts a putative Sp1 transcription factor binding site (300126.0008). An intronic change was detected that resulted in the partial incorporation of a portion of intron 1 into the mRNA (300126.0009). This was the first report of DKC1 mutations that are predicted to affect the level of expression of dyskerin rather than its amino acid sequence. This suggests that a decrease in the amount of the normal protein may cause the disorder.
Knight et al. (1999) identified mutations in the DKC1 gene in patients with Hoyeraal-Hreidarsson syndrome (305000), a severe clinical variant of dyskeratosis congenita; see 300126.0010-300126.0011.
In 5 male Japanese patients with presumed X-linked dyskeratosis congenita, Kanegane et al. (2005) identified 4 mutations in the DKC1 gene, including 2 novel missense mutations, Q31K (300126.0013) and T357A (300126.0014).
Cataracts, Hearing Impairment, Nephrotic Syndrome, and Enterocolitis 1
In 1 affected male and 6 affected females from a large multigenerational family (family A) with cataracts, hearing impairment, nephrotic syndrome, and enterocolitis-1 (CHINE1; 301108), Balogh et al. (2020) identified a hemizygous or heterozygous missense mutation in the DKC1 gene (E206K; 300126.0016). Two unaffected females also carried the mutation, indicating incomplete penetrance in females. The mutation occurred at a conserved residue in the DKC1-NOP10 (606471) interface in a region distinct from those implicated in DKCX. Molecular modeling and in vitro studies showed that the mutation altered the hydrogen binding between dyskerin and NOP10, disrupted the catalytic pseudouridylation site, and altered the pseudouridylation capacity of the snoRNP complex. Expression of the E206K mutation in dkc1-null zebrafish was unable to fully rescue the developmental phenotype, indicating that it is a hypomorphic mutation (see ANIMAL MODEL). Despite the finding of shortened telomeres in the affected females, the authors concluded that a pseudouridylation defect causing ribosomal dysfunction is the primary driver of this unique phenotype.
He et al. (2002) used the inducible Cre/loxP system to produce deletions in the murine Dkc1 gene in early embryogenesis. A large deletion lacking exons 12-15 and a small deletion lacking only the last exon were produced. They found that both deletions showed a parent-of-origin effect with 100% embryonic lethality when the mutation occurred on the maternal Dkc1. Embryonic analysis at days 7.5 and 9.5 of gestation showed no male embryos carrying either deletion, whereas females with maternally derived deletions died around day 9.5 of gestation, with degeneration of the extra embryonic tissue, in which the paternal X chromosome was inactivated. Female mice carrying the deletion in the paternally derived Dkc1 showed extreme skewing of X inactivation with the wildtype X chromosome active in all cells. Since mice with no telomerase are viable in the first generations, the lethality observed by He et al. (2002) was unlikely to be caused by the effects of mutated dyskerin on telomerase activity.
Ruggero et al. (2003) generated hypomorphic Dkc1 mutant mice. that recapitulated the DKC (305000) phenotype in the first and second generations. Cells from hemizygous male and heterozygous female mutant mice displayed a decreased level of Dkc1 expression (4-fold and 2-fold, respectively). Hypomorphic Dkc1 cells from the first and second generation were impaired in ribosomal RNA pseudouridylation before the onset of disease. Reduction of telomere length in hypomorphic mice became evident only in later generations. Ruggero et al. (2003) concluded that deregulated ribosome function is important in the initiation of dyskeratosis congenita, whereas telomere shortening may modify and/or exacerbate dyskeratosis congenita.
To test the extent to which disruption of pseudouridylation or telomerase activity may contribute to the pathogenesis of dyskeratosis congenita, Mochizuki et al. (2004) introduced 2 dyskerin mutations into murine embryonic stem cells: ala353 to val (A353V; 300126.0006), which is the most frequent mutation in patients with X-linked dyskeratosis congenita, and gly402 to glu (G402E; 300126.0005), which had been identified in a single patient. The A353V, but not the G402E, mutation led to severe destabilization of telomerase RNA, reduction in telomerase activity, and a significant continuous loss of telomere length with increasing number of cell divisions during in vitro culture. Both mutations caused a defect in overall pseudouridylation and a small but detectable decrease in the rate of pre-ribosomal RNA processing. In addition, both mutant embryonic stem cell lines showed a decrease in the accumulation of a subset of H/ACA small nucleolar RNAs, correlating with a significant decrease in site-specific pseudouridylation efficiency. Mochizuki et al. (2004) concluded that point mutations in dyskerin may affect both the telomerase and pseudouridylation pathways and that the extent to which these functions are altered can vary for different mutations.
Using an unbiased proteomics strategy, Yoon et al. (2006) discovered a specific defect in IRES (internal ribosome entry site)-dependent translation in Dkc1 mutated mice and in cells from X-linked dyskeratosis congenita patients. This defect results in impaired translation of mRNAs containing IRES elements, including those encoding the tumor suppressor p27(Kip1) (600778) and the antiapoptotic factors Bcl-xl (600039) and XIAP (300079). Moreover, ribosomes derived from Dkc1 mutated mice were unable to direct translation from IRES elements present in viral mRNAs. Yoon et al. (2006) concluded that their findings revealed a potential mechanism by which defective ribosome activity leads to disease and cancer.
Balogh et al. (2020) found that knockdown of the dkc1 gene in zebrafish resulted in death at 5 days postfertilization. Ocular sections of dkc1-null larvae showed opaque lenses resembling cataracts, increased neuroepithelial progenitor cells, and retinal cell proliferation indicative of a cell-cycle defect. Mutant animals had microphthalmia, impaired development of the inner ear and intestinal compartments of the gut, hypoplastic pronephros with reduced podocytes, hematopoietic defects, defective jaw-cartilage development, and a disorganized pineal gland. These features were reminiscent of the human disorder CHINE1 (301108). Telomere shortening was not observed. Expression of wildtype human DKC1 could rescue the zebrafish phenotype, but expression of the E206K variant (300126.0016) only showed limited rescue. There was also evidence of impaired pseudouridylation of 18S rRNA and defects in ribosomal biogenesis and function.
In a patient with dyskeratosis congenita (DKCX; 305000), Heiss et al. (1998) identified a T-to-G transversion at nucleotide 198 of the cDNA, resulting in an phe36-to-val (F36V) amino acid substitution in dyskerin. The amino acid is phenylalanine in the homologous protein in both rat and yeast. The family had previously been reported by Devriendt et al. (1997).
In a patient with dyskeratosis congenita (DKCX; 305000), Heiss et al. (1998) found deletion of nucleotides 201-203 (CTT), leading to deletion of leucine-37 from dyskerin.
In a patient with dyskeratosis congenita (DKCX; 305000), Heiss et al. (1998) identified a C-to-G transversion at nucleotide 211, resulting in a pro40-to-arg (P40R) amino acid substitution in dyskerin. The family had previously been reported by Connor et al. (1986).
In a patient with dyskeratosis congenita (DKCX; 305000), Heiss et al. (1998) identified a leu72-to-tyr (L72Y) mutation resulting from a change of nucleotides 306 and 307 from CT to TA.
In a patient with dyskeratosis congenita (DKCX; 305000), Heiss et al. (1998) described a G-to-A transition at nucleotide 1297 of the full-length DKC1 cDNA, resulting in a gly402-to-glu (G402Q) amino acid substitution in dyskerin. The family had previously been reported by Dokal et al. (1992).
In a study that demonstrated missense mutations to be the predominant abnormality in the DKC1 gene leading to dyskeratosis congenita (DKCX; 305000), Knight et al. (1999) found that the missense mutation ala353 to val (A353V) was present in 11 of 21 families in which they could demonstrate a mutation. The amino acid substitution was due to a 1058C-T transition in exon 11. It was found in both sporadic cases and multiplex families and in patients in the United Kingdom, Italy, France, United States, and Spain. In at least 5 instances, the mutation was de novo in the proband; in another case it was de novo in grandparents. Heiss et al. (2001) found the A353V mutation in another case of DKCX.
Yaghmai et al. (2000) reported a patient with striking features of Hoyeraal-Hreidarsson syndrome and DKC who carried the A353V mutation. Yaghmai et al. (2000) concluded that Hoyeraal-Hreidarsson syndrome may be a severe form of DKC in which affected individuals die before characteristic mucocutaneous features develop.
Grozdanov et al. (2009) showed that the A353V mutation resulted in decreased binding affinity for SHQ1 (613663), likely resulting in loss of NAP57 due to degradation.
Vulliamy et al. (1999) presented a case of dyskeratosis congenita (DKCX; 305000) caused by a 2-kb deletion that removed the last exon of the DKC1 gene. Normal levels of mRNA were produced from the deleted gene, with the transcripts using a cryptic polyadenylation site in the antisense strand of the adjacent MPP1 gene (305360), which is normally located 1 kb downstream of DKC1 in a tail-to-tail orientation. The predicted truncated protein lacked a lysine-rich peptide that is less conserved than the rest of the dyskerin molecule and is dispensable in yeast, supporting the contention that it may retain some activity and that null mutations at this locus may be lethal. The affected boy had an unaffected brother with the same haplotype around the DKC1 gene and a sister who was heterozygous for the deletion. The authors concluded, therefore, that the mother must be a germline mosaic with respect to this deletion. Investigation of her blood cells and other somatic tissues showed that a small proportion of these cells also carried the deletion, making her a somatic mosaic and indicating that the deletion took place early in development.
In a patient with dyskeratosis congenita (DKCX; 305000), Knight et al. (2001) found a mutation in the promoter region of the DKC1 gene: -141C-G. The mutation disrupts one of the Sp1 transcription factor binding sites. Salowsky et al. (2002) showed that the core promoter region of the DKC1 gene was critical for the basal level of transcription that lies at -10 to -180. They showed that this mutation is in one of the Sp1 binding sites and that it reduces promoter activity.
In an affected male from a family with dyskeratosis congenita (DKCX; 305000) studied by Devriendt et al. (1997), Knight et al. (2001) found an anomalous transcript resulting from the incorporation of 246 bp of intron 1. Sequencing of the intron flanking the 'cryptic exon' revealed a single nucleotide change (IVS1 +592C-G). This sequence change created a cryptic donor splice site that resulted in the partial incorporation of part of intron 1 into the dyskerin mRNA. The fact that the reading frame was disrupted by an early stop codon strongly suggested that the 'cryptic exon' did not correspond to a functional alternatively spliced transcript.
In a family segregating Hoyeraal-Hreidarsson syndrome, the severe variant of DKC (DKCX; 305000), Knight et al. (1999) identified a C-to-T change at nucleotide 146 in exon 3 of the DKC1 gene, resulting in a thr49-to-met (T49M) substitution. Heiss et al. (2001) identified the same mutation in a patient with DKCX. Grozdanov et al. (2009) showed that the T49M mutation resulted in increased binding affinity for SHQ1 (613663), likely resulting in NAP57 sequestration.
Lim et al. (2014) identified a T49M mutation (rs121912304) in the DKC1 gene in 2 Korean brothers with DKCX presenting as Hoyeraal-Hreidarsson syndrome. One of the boys died at age 3 years after a bone marrow transplant. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present in the unaffected mother. Functional studies of the variant were not performed.
In a family originally reported by Aalfs et al. (1995) with Hoyeraal-Hreidarsson syndrome, the severe form of dyskeratosis congenita (DKCX; 305000), Knight et al. (1999) identified an A-to-G change at nucleotide 361 in exon 5 of the DKC1 gene, resulting in a ser121-to-gly (S121G) substitution. Grozdanov et al. (2009) showed that the S121G mutation did not affect SHQ1 (613663) binding, consistent with its location in the catalytic domain and suggesting that the mutation affects the catalytic activity of NAP57.
In a Sardinian infant with X-linked Hoyeraal-Hreidarsson syndrome (DKCX; 305000) in whom the disorder was characterized by severe combined immunodeficiency and bone marrow failure, Cossu et al. (2002) described a 113T-C transition in the DKC1 gene, resulting in an ile38-to-thr (I38T) mutation. Treatment with a sib bone marrow transplantation was associated with low toxicity, prompt engraftment with adequate immune reconstitution, and full donor hemopoiesis.
In a Japanese patient with dyskeratosis congenita (DKCX; 305000), Kanegane et al. (2005) detected a 91C-A transversion in exon 3 of the DKC1 gene that resulted in a gln31-to-lys (Q31K) amino acid substitution in dyskerin.
In a Japanese patient with dyskeratosis congenita (DKCX; 305000), Kanegane et al. (2005) detected a 1069A-G transition in exon 11 of the DKC1 gene that resulted in a thr357-to-ala (T357A) amino acid substitution in dyskerin.
In an Italian boy with Hoyeraal-Hreidarsson syndrome, the severe form of dyskeratosis congenita (DKCX; 305000), Pearson et al. (2008) identified a hemizygous G-to-A transition in intron 12 of the DKC1 gene, resulting in premature termination. He had poor intrauterine and postnatal growth, developed persistent thrombocytopenia, and died at age 2 years. His unaffected mother was a carrier of the mutation.
In 1 affected male and 6 variably affected females from a large multigenerational family (family A) with cataracts, hearing impairment, nephrotic syndrome, and enterocolitis-1 (CHINE1; 301108), Balogh et al. (2020) identified a hemizygous (in the male patient) or heterozygous (in the female patients) c.616G-A transition in the DKC1 gene, resulting in a glu206-to-lys (E206K) substitution at a conserved residue in the catalytic pseudouridylation site. The mutation, which was found by a combination of linkage analysis and candidate gene sequencing, was not present in the gnomAD database. The mutation segregated with the disorder in the family, although 2 unaffected females also carried the mutation, indicating incomplete penetrance in females. The mutation occurred in the DKC1-NOP10 (606471) interface in a region distinct from those implicated in DKCX. Although the binding interaction with NOP10 was maintained, molecular modeling and in vitro studies showed that the E206K mutation altered the hydrogen binding between dyskerin and NOP10, disrupted the catalytic pseudouridylation site, and altered the pseudouridylation capacity of the snoRNP complex. Peripheral blood cells from the most severely affected female in this family (IV:4) showed a pseudouridylation defect of 18S rRNA that was not observed in patient fibroblasts, suggesting a tissue-specific effect. Expression of the E206K mutation in dkc1-null zebrafish was unable to fully rescue the developmental phenotype, indicating that it is a hypomorphic mutation (see ANIMAL MODEL). Despite the finding of shortened telomeres in the affected females, the authors concluded that a pseudouridylation defect causing ribosomal dysfunction is the primary driver of this unique phenotype.
Aalfs, C. M., van den Berg, H., Barth, P. G., Hennekam, R. C. M. The Hoyeraal-Hreidarsson syndrome: the fourth case of a separate entity with prenatal growth retardation, progressive pancytopenia and cerebellar hypoplasia. Europ. J. Pediat. 154: 304-308, 1995. [PubMed: 7607282] [Full Text: https://doi.org/10.1007/BF01957367]
Balogh, E., Chandler, J. C., Varga, M., Tahoun, M., Menyhard, D. K., Schay, G., Goncalves, T., Hamar, R., Legradi, R., Szekeres, A., Gribouval, O., Kleta, R., and 45 others. Pseudouridylation defect due to DKC1 and NOP10 mutations causes nephrotic syndrome with cataracts, hearing impairment, and enterocolitis. Proc. Nat. Acad. Sci. 117: 15137-15147, 2020. [PubMed: 32554502] [Full Text: https://doi.org/10.1073/pnas.2002328117]
Cohen, S. B., Graham, M. E., Lovrecz, G. O., Bache, N., Robinson, P. J., Reddel, R. R. Protein composition of catalytically active human telomerase from immortal cells. Science 315: 1850-1853, 2007. [PubMed: 17395830] [Full Text: https://doi.org/10.1126/science.1138596]
Connor, J. M., Gatherer, D., Gray, F. C., Pirrit, L. A., Affara, N. A. Assignment of the gene for dyskeratosis congenita to Xq28. Hum. Genet. 72: 348-351, 1986. [PubMed: 3009302] [Full Text: https://doi.org/10.1007/BF00290963]
Cossu, F., Vulliamy, T. J., Marrone, A., Badiali, M., Cao, A., Dokal, I. A novel DKC1 mutation, severe combined immunodeficiency (T+B-NK-SCID) and bone marrow transplantation in an infant with Hoyeraal-Hreidarsson syndrome. Brit. J. Haemat. 119: 765-768, 2002. [PubMed: 12437656] [Full Text: https://doi.org/10.1046/j.1365-2141.2002.03822.x]
Devriendt, K., Matthijs, G., Legius, E., Schollen, E., Blockmans, D., van Geet, C., Degreef, H., Cassiman, J.-J., Fryns, J.-P. Skewed X-chromosome inactivation in female carriers of dyskeratosis congenita. Am. J. Hum. Genet. 60: 581-587, 1997. [PubMed: 9042917]
Dokal, I., Bungey, J., Williamson, P., Oscier, D., Hows, J., Luzzatto, L. Dyskeratosis congenita fibroblasts are abnormal and have unbalanced chromosomal rearrangements. Blood 80: 3090-3096, 1992. [PubMed: 1361371]
Grozdanov, P. N., Fernandez-Fuentes, N., Fiser, A., Meier, U. T. Pathogenic NAP57 mutations decrease ribonucleoprotein assembly in dyskeratosis congenita. Hum. Molec. Genet. 18: 4546-4551, 2009. [PubMed: 19734544] [Full Text: https://doi.org/10.1093/hmg/ddp416]
Hassock, S., Vetrie, D., Giannelli, F. Mapping and characterization of the X-linked dyskeratosis congenita (DKC) gene. Genomics 55: 21-27, 1999. [PubMed: 9888995] [Full Text: https://doi.org/10.1006/geno.1998.5600]
He, J., Navarrete, S., Jasinski, M., Vulliamy, T., Dokal, I., Bessler, M., Mason, P. J. Targeted disruption of Dkc1, the gene mutated in X-linked dyskeratosis congenita, causes embryonic lethality in mice. Oncogene 21: 7740-7744, 2002. [PubMed: 12400016] [Full Text: https://doi.org/10.1038/sj.onc.1205969]
Heiss, N. S., Knight, S. W., Vulliamy, T. J., Klauck, S. M., Wiemann, S., Mason, P. J., Poustka, A., Dokal, I. X-linked dyskeratosis congenita is caused by mutations in a highly conserved gene with putative nucleolar functions. Nature Genet. 19: 32-38, 1998. [PubMed: 9590285] [Full Text: https://doi.org/10.1038/ng0598-32]
Heiss, N. S., Megarbane, A., Klauck, S. M., Kreuz, F. R., Makhoul, E., Majewski, F., Poustka, A. One novel and two recurrent missense DKC1 mutations in patients with dyskeratosis congenita (DKC). Genet. Counsel. 12: 129-136, 2001. [PubMed: 11491307]
Kanegane, H., Kasahara, Y., Okamura, J., Hongo, T., Tanaka, R., Nomura, K., Kojima, S., Miyawaki, T. Identification of DKC1 gene mutations in Japanese patients with X-linked dyskeratosis congenita. Brit. J. Haemat. 129: 432-434, 2005. [PubMed: 15842668] [Full Text: https://doi.org/10.1111/j.1365-2141.2005.05473.x]
Knight, S. W., Heiss, N. S., Vulliamy, T. J., Aalfs, C. M., McMahon, C., Richmond, P., Jones, A., Hennekam, R. C. M., Poustka, A., Mason, P. J., Dokal, I. Unexplained aplastic anaemia, immunodeficiency, and cerebellar hypoplasia (Hoyeraal-Hreidarsson syndrome) due to mutations in the dyskeratosis congenita gene, DKC1. Brit. J. Haemat. 107: 335-339, 1999. [PubMed: 10583221] [Full Text: https://doi.org/10.1046/j.1365-2141.1999.01690.x]
Knight, S. W., Heiss, N. S., Vulliamy, T. J., Greschner, S., Stavrides, G., Pai, G. S., Lestringant, G., Varma, N., Mason, P. J., Dokal, I., Poustka, A. X-linked dyskeratosis congenita is predominantly caused by missense mutations in the DKC1 gene. Am. J. Hum. Genet. 65: 50-58, 1999. [PubMed: 10364516] [Full Text: https://doi.org/10.1086/302446]
Knight, S. W., Vulliamy, T. J., Morgan, B., Devriendt, K., Mason, P. J., Dokal, I. Identification of novel DKC1 mutations in patients with dyskeratosis congenita: implications for pathophysiology and diagnosis. Hum. Genet. 108: 299-303, 2001. [PubMed: 11379875] [Full Text: https://doi.org/10.1007/s004390100494]
Lim, B. C., Yoo, S.-K., Lee, S., Shin, J.-Y., Hwang, H., Chae, J. H., Hwang, Y. S., Seo, J.-S., Kim, J.-I., Kim, K. J. Hoyeraal-Hreidarsson syndrome with a DKC1 mutation identified by whole-exome sequencing. Gene 546: 425-429, 2014. [PubMed: 24914498] [Full Text: https://doi.org/10.1016/j.gene.2014.06.011]
Luzzatto, L., Karadimitris, A. Dyskeratosis and ribosomal rebellion. Nature Genet. 19: 6-7, 1998. [PubMed: 9590276] [Full Text: https://doi.org/10.1038/ng0598-6]
Machado-Pinilla, R., Sanchez-Perez, I., Murguia, J. R., Sastre, L., Perona, R. A dyskerin motif reactivates telomerase activity in X-linked dyskeratosis congenita and in telomerase-deficient human cells. Blood 111: 2606-2614, 2008. [PubMed: 18057229] [Full Text: https://doi.org/10.1182/blood-2007-04-083261]
McGrath, J. A. Dyskeratosis congenita: new clinical and molecular insights into ribosome function. Lancet 353: 1204-1205, 1999. [PubMed: 10217077] [Full Text: https://doi.org/10.1016/S0140-6736(99)00011-2]
Mitchell, J. R., Wood, E., Collins, K. A telomerase component is defective in the human disease dyskeratosis congenita. Nature 402: 551-555, 1999. [PubMed: 10591218] [Full Text: https://doi.org/10.1038/990141]
Mochizuki, Y., He, J., Kulkarni, S., Bessler, M., Mason, P. J. Mouse dyskerin mutations affect accumulation of telomerase RNA and small nucleolar RNA, telomerase activity, and ribosomal RNA processing. Proc. Nat. Acad. Sci. 101: 10756-10761, 2004. [PubMed: 15240872] [Full Text: https://doi.org/10.1073/pnas.0402560101]
Montanaro, L., Chilla, A., Trere, D., Pession, A., Govoni, M., Tazzari, P. L, Derenzini, M. Increased mortality rate and not impaired ribosomal biogenesis is responsible for proliferative defect in dyskeratosis congenita cell lines. J. Invest. Derm. 118: 193-198, 2002. [PubMed: 11851894] [Full Text: https://doi.org/10.1046/j.0022-202x.2001.01634.x]
Pearson, T., Curtis, F., Al-Eyadhy, A., Al-Tamemi, S., Mazer, B., Dror, Y., Abish, S., Bale, S., Compton, J., Ray, R., Scott, P., Der Kaloustian, V. M. An intronic mutation in DKC1 in an infant with Hoyeraal-Hreidarsson syndrome. (Letter) Am. J. Med. Genet. 146A: 2159-2161, 2008. [PubMed: 18627054] [Full Text: https://doi.org/10.1002/ajmg.a.32412]
Pogacic, V., Dragon, F., Filipowicz, W. Human H/ACA small nucleolar RNPs and telomerase share evolutionarily conserved proteins NHP2 and NOP10. Molec. Cell. Biol. 20: 9028-9040, 2000. [PubMed: 11074001] [Full Text: https://doi.org/10.1128/MCB.20.23.9028-9040.2000]
Rashid, R., Liang, B., Baker, D. L., Youssef, O. A., He, Y., Phipps, K., Terns, R. M., Terns, M. P., Li, H. Crystal structure of a Cbf5-Nop10-Gar1 complex and implications in RNA-guided pseudouridylation and dyskeratosis congenita. Molec. Cell 21: 249-260, 2006. [PubMed: 16427014] [Full Text: https://doi.org/10.1016/j.molcel.2005.11.017]
Ruggero, D., Grisendi, S., Piazza, F., Rego, E., Mari, F., Rao, P. H., Cordon-Cardo, C., Pandolfi, P. P. Dyskeratosis congenita and cancer in mice deficient in ribosomal RNA modification. Science 299: 259-262, 2003. [PubMed: 12522253] [Full Text: https://doi.org/10.1126/science.1079447]
Salowsky, R., Heiss, N. S., Benner, A., Wittig, R., Poustka, A. Basal transcription activity of the dyskeratosis congenita gene is mediated by Sp1 and Sp3 and a patient mutation in a Sp1 binding site is associated with decreased promoter activity. Gene 293: 9-19, 2002. [PubMed: 12137939] [Full Text: https://doi.org/10.1016/s0378-1119(02)00725-4]
Venteicher, A. S., Abreu, E. B., Meng, Z., McCann, K. E., Terns, R. M., Veenstra, T. D., Terns, M. P., Artandi, S. E. A human telomerase holoenzyme protein required for Cajal body localization and telomere synthesis. Science 323: 644-648, 2009. [PubMed: 19179534] [Full Text: https://doi.org/10.1126/science.1165357]
Vulliamy, T. J., Knight, S. W., Heiss, N. S., Smith, O. P., Poustka, A., Dokal, I., Mason, P. J. Dyskeratosis congenita caused by a 3-prime deletion: germline and somatic mosaicism in a female carrier. Blood 94: 1254-1260, 1999. [PubMed: 10438713]
Wong, J. M. Y., Collins, K. Telomerase RNA level limits telomere maintenance in X-linked dyskeratosis congenita. Genes Dev. 20: 2848-2858, 2006. [PubMed: 17015423] [Full Text: https://doi.org/10.1101/gad.1476206]
Yaghmai, R., Kimyai-Asadi, A., Rostamiani, K., Heiss, N. S., Poustka, A., Eyaid, W., Bodurtha, J., Nousari, H. C., Hamosh, A., Metzenberg, A. Overlap of dyskeratosis congenita with the Hoyeraal-Hreidarsson syndrome. J. Pediat. 136: 390-393, 2000. [PubMed: 10700698] [Full Text: https://doi.org/10.1067/mpd.2000.104295]
Yoon, A., Peng, G., Brandenburger, Y., Zollo, O., Xu, W., Rego, E., Ruggero, D. Impaired control of IRES-mediated translation in X-linked dyskeratosis congenita. Science 312: 902-905, 2006. Note: Erratum: Science 313: 1238 only, 2006. [PubMed: 16690864] [Full Text: https://doi.org/10.1126/science.1123835]