Alternative titles; symbols
Other entities represented in this entry:
SNOMEDCT: 707276009, 708536001; ORPHA: 1775, 3322; DO: 0070025;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xq28 | Dyskeratosis congenita, X-linked | 305000 | X-linked recessive | 3 | DKC1 | 300126 |
A number sign (#) is used with this entry because of evidence that X-linked dyskeratosis congenita (DKCX) is caused by mutation in the dyskerin gene (DKC1; 300126) on chromosome Xq28.
Dyskeratosis congenita (DKC) is classically defined by the triad of abnormal skin pigmentation, nail dystrophy, and leukoplakia of the oral mucosa. It is characterized by short telomeres. Progressive bone marrow failure occurs in over 80% of cases and is the main cause of early mortality. The phenotype is highly variable, and affected individuals may have multiple additional features, including pulmonary fibrosis, liver cirrhosis, hepatopulmonary syndrome, premature hair loss and/or graying, osteoporosis, atresia of the lacrimal ducts, gastrointestinal disease (esophageal strictures or enteropathy), and learning difficulties. Males may have testicular atrophy. Predisposition to malignancy, including hematologic malignancy and squamous cell carcinoma, is an important feature. The disorder is caused by defects in the maintenance of telomeres (summary by Kirwan and Dokal, 2008; Gorgy et al., 2015; Schratz et al., 2023).
Hoyeraal-Hreidarsson syndrome (HHS) refers to a clinically severe variant of DKC that is characterized by multisystem involvement and early onset in utero. Patients with HHS can show intrauterine growth retardation, microcephaly, delayed development, bone marrow failure, immunodeficiency, cerebellar hypoplasia, immune defects (B-cell lymphopenia and hypogammaglobulinemia), and gastrointestinal manifestations, including enterocolitis and enteropathy. Death often occurs in childhood (summary by Walne et al., 2013).
For a discussion of genetic heterogeneity of dyskeratosis congenita, see DKCA1 (127550).
Sirinavin and Trowbridge (1975) reported a large kindred with X-linked DKC. Pancytopenia and malignancy were features, and opportunistic infections were also a major complication. Nail dystrophy, reticulated atrophic telangiectatic hyper- and hypopigmented skin lesions, oral leukoplakia, and impaired intellectual development were described. An extensive review of the literature was provided.
Connor and Teague (1981) reported an affected kindred, and noted 3 previously unreported complications: Hodgkin disease, pancreatic adenocarcinoma, and deafness. Normal chromosomal stability was found in the 3 patients studied. Studies uncovered no early generalized defect of cell-mediated immunity.
Womer et al. (1983) reported 2 brothers who showed reticular hyperpigmentation, dystrophic nails, oral leukoplakia, and aplastic anemia. Less common features included prenatal and postnatal growth retardation, mental retardation, elevated immunoglobulin levels, and gastrointestinal hemorrhage from mucosal ulcerations. 'New' features were intracranial calcifications and nutmeg-like cirrhosis of the liver. No increased chromosomal breakage was noted. Death occurred at ages 18 and 14 years.
Davidson and Connor (1988) provided an extensive review of 104 published cases of which 51 had previously been reviewed by Sirinavin and Trowbridge (1975).
Phillips et al. (1992) described a 5-year-old boy who was treated with bone marrow transplantation for aplastic anemia at the age of 2 years. The diagnosis of dyskeratosis congenita was not made until 18 months after the bone marrow transplant. He had diffuse nonscarring alopecia and problems related to bilateral lacrimal duct blockage. At the age of 5 years, all nails were hypoplastic and irregular, and he had reticulate hyperpigmentation on his neck. He required a hearing aid and had poor vision in one eye. Lacrimal duct stenosis is said to be present in about 80% of cases. In 70%, pancytopenia is the cause of death. Because of a previously widely held view that the outcome of bone marrow transplantation in this disorder is poor, this treatment option was sometimes not considered when pancytopenia developed. Phillips et al. (1992) suggested that the results may be satisfactory if radiation is avoided.
Bone marrow failure has been reported in approximately 50% of cases of dyskeratosis congenita (Dokal, 1996), and in some patients symptoms related to aplastic anemia may precede the diagnosis of DKC (Forni et al., 1993).
Caux et al. (1996) presented a patient and reviewed the pathogenesis of the disorder.
Merchant et al. (1998) described the changes of chronic keratoconjunctivitis in a case of congenital dyskeratosis thought to be autosomal dominant with 'variable penetration.' In general, the disorder is more likely to be X-linked, and the family history suggested that this was the case with partial expression in heterozygous females. The patient was a 58-year-old man from Puerto Rico. In addition to chronic cicatrizing keratoconjunctivitis, which was said to have been a problem since 5 years of age, he had reticulate pigmentation of the skin, dystrophic nails, leukoplakia, alopecia, dental problems resulting in tooth loss, and thrombocytopenia. The patient's mother had a mild form of the disorder with limited skin involvement, and 2 brothers had significant skin pigmentation and nail dystrophy. One of the brothers also had a history of tongue cancer. The patient had 1 son who had no manifestations of the disease but 2 of his 3 daughters had classic skin and nail findings of congenital dyskeratosis, and the third daughter had subtle skin changes. One of the daughter's sons, who was 17 years old, had early pigmentary skin changes and significant thrombocytopenia.
In the Dyskeratosis Congenita Registry at the Hammersmith Hospital in London, 46 families were recruited (Knight et al., 1998). Of 83 patients, 76 were male, suggesting that the major form of DKC is X-linked. In addition to a variety of noncutaneous abnormalities, most of the patients (93%) had bone marrow failure, which was the principal cause (71%) of early mortality. Some patients also developed myelodysplasia and acute myeloid leukemia. Pulmonary abnormalities were present in 19% of patients.
Parry et al. (2011) reported a large family of Irish ancestry with X-linked inheritance of adult-onset pulmonary fibrosis. Clinical history revealed that affected members also had features suggestive of DKC, including nail dystrophy, skin hyperpigmentation, and liver cirrhosis. One patient died of squamous cell carcinoma at age 34 years, but there was no family history of aplastic anemia. Four affected males had telomere lengths at or below the 1st centile compared to controls, as well as low levels of telomerase RNA. Western blot analysis showed low levels of dyskerin in affected males, but sequencing of the DKC1 gene did not identify any pathogenic mutations. However, genomewide linkage analysis identified a 47-cM peak on chromosome Xq28 (lod score of 3.25), and obligate carriers females showed skewed X inactivation. The findings indicated that intact levels of dyskerin, in the absence of coding mutations, are essential for in vito telomere maintenance, and that a defect in dyskerin levels is sufficient to cause telomere-mediated disease. Parry et al. (2011) emphasized the high frequency of pulmonary fibrosis as a manifestation of the disorder in this family. Affected individuals died as adults, suggesting that pulmonary disease may represent an attenuated, adult-onset telomere phenotype.
Jonassaint et al. (2013) identified significant gastrointestinal disease in 6 (16%) of 38 individuals from a registry of patients with short telomere syndromes due to various genetic defects. Two of these patients had mutations in the DKC1 gene. Patient 2 was a 3-year-old boy with a diagnosis of Hoyeraal-Hreidarsson syndrome (HHS) and patient 6 was a 34-year-old man with classic features of DKC. Both had dysphagia due to severe esophageal stenosis with a membranous web that partially occluded the lumen. Balloon dilation resulted in clinical improvement in both patients. Patient 6 also had atrophic gastritis with parietal cell dropout, villous blunting in the bowel, increased epithelial apoptosis in the duodenum, and duodenal and colonic intraepithelial lymphocytosis. A review of the literature identified additional patients with DKC and HHS who had gastrointestinal disease; some of these patients had mutations in the DKC1 gene, but the gene defect in other patients was not reported. Overall, intestinal disease presented earlier and was more severe in younger patients with HHS compared to those with classic DKC. Dysphagia due to esophageal stricture and stenosis was the most common upper GI feature; it was observed mainly in patients with DKC, although a few patients had HHS. Chronic diarrhea with failure to thrive due to enteropathy and enterocolitis was the most common lower GI feature; it was observed mainly in younger patients with HHS and was often a presenting feature. Histopathologic findings included pancolitis, atrophic mucosa, gland dropout, lamina propria fibrosis, intraepithelial lymphocytosis, and epithelial cell apoptosis. The disease course in HHS patients with lower GI disease was sometimes life-threatening, requiring total parenteral nutrition or colectomy. All patients with HHS and intestinal disease had a concurrent B-cell lymphopenia and/or hypogammaglobulinemia. The findings suggested that telomere dysfunction disrupts the epithelial integrity of the GI tract.
Gorgy et al. (2015) diagnosed hepatopulmonary syndrome (HPS) in 2 unrelated males (patients 1 and 6) with X-linked DKC who had short telomeres and progressive dyspnea without parenchymal lung disease or fibrosis. One patient was diagnosed at age 8 years and died at age 17; the other was diagnosed at age 34 and died at 40. Features included cyanosis, digital clubbing, splenomegaly, elevated liver enzymes, portal hypertension, ascites, and variceal bleeding. Both had evidence of intra- and extra-pulmonary arteriovascular fistulas that caused shunt physiology. Patient 6 had nodular regenerative hyperplasia on liver biopsy. Variable syndromic features found in these patients included bone marrow failure and skin telangiectasia. The authors concluded that HPS can cause dyspnea in telomerase gene mutation carriers.
Schratz et al. (2023) identified 16 invasive solid tumors in 14 of 226 adults with short telomere syndromes due to mutations in several genes, including DKC1. Nearly all (88%) of the tumors were derived from the squamous cell epithelium, most commonly of the head and neck, followed by anal squamous cell carcinoma and skin squamous cell carcinoma. In contrast, there was a lower than expected number of common age-related solid cancers among these patients. Most of the patients who developed squamous cell solid tumors were male. Development of the tumors was associated with CD4+ T-cell lymphopenia, suggesting impaired tumor surveillance by T cells and age-related T-cell exhaustion. Of note, all 3 anal cancers and 1 laryngeal cancer were associated with HPV infection, and 4 of 10 patients with T-cell lymphopenia had secondary causes for the lymphopenia (lung or liver transplant or iatrogenic immunosuppression).
Hoyeraal-Hreidarsson Syndrome
Hoyeraal et al. (1970) reported 2 brothers with prenatal growth retardation, microcephaly, mental retardation with spastic paresis and ataxia, pancerebellar hypoplasia, thrombocytopenia, and bone marrow hypoplasia. Hreidarsson et al. (1988) reported a single affected male and proposed that the disorder is autosomal recessive because the parents were consanguineous. The brothers of Hoyeraal et al. (1970) died at 23 and 42 months of age; the patient of Hreidarsson et al. (1988) died at 23 months of age. Aalfs et al. (1995) reported a single case, a male with nonconsanguineous parents who was still alive at the age of 4 years. Like the case of Hreidarsson et al. (1988), the patient had pancytopenia, as well as intrauterine growth retardation, microcephaly, developmental delay, spastic paresis, ataxia, and cerebellar hypoplasia. Berthet et al. (1994) and Berthet et al. (1995) suggested that immunodeficiency is a feature of this syndrome.
Reardon et al. (1994) suggested that this is the same condition as the autosomal recessive congenital intrauterine infection-like syndrome, or pseudo-TORCH syndrome (251290). Aalfs and Hennekam (1995) described several differences between the 2 syndromes. Patients with Hoyeraal-Hreidarsson syndrome show only growth retardation and microcephaly in the first months of life, whereas those with the pseudo-TORCH syndrome have symptoms resembling TORCH infection shortly after birth, including hepatosplenomegaly. Furthermore, in the intrauterine infection-like syndrome, the neonatally present thrombocytopenia resolves within a year if the child survives, whereas in the Hoyeraal-Hreidarsson syndrome the first symptoms of pancytopenia do not occur before the age of 5 months and continue to increase for years. The cerebellum is proportionately small in Hoyeraal-Hreidarsson syndrome, whereas the cerebral abnormalities are more severe in the pseudo-TORCH syndrome.
Ohga et al. (1997) summarized 6 reported cases of Hoyeraal-Hreidarsson syndrome.
Mahmood et al. (1998) described 2 sibs with low birthweight, failure to thrive, chronic persistent tongue ulceration, severe truncal ataxia, and pancytopenia without either telangiectasia or chromosomal instability. One sib died from sepsis and the cerebellum demonstrated reduced cellularity of the molecular and granular layers with relative preservation of Purkinje cells and minimal gliosis. The surviving sib showed hematologic progression to a myelodysplastic disorder. There was no evidence of chromosomal instability following exposure of fibroblasts and lymphocytes to irradiation. Monosomy-7 was not present in the surviving sib. Mahmood et al. (1998) suggested the diagnosis of Hoyeraal-Hreidarsson syndrome.
Yaghmai et al. (2000) reported a 4-year-old boy with pancytopenia and oral ulcers who was born at 32 weeks' gestation with intrauterine growth retardation. He had developed esophageal strictures and gastric ulcers, and also had moderate hypoplasia of the midline cerebellum and Dandy-Walker variant (220200). He had microcephaly, thin, brittle scalp hair, 20-nail dystrophy, and subtle reticulated hyperpigmentation of the shoulder and arms. This child had striking features of both Hoyeraal-Hreidarsson syndrome and X-linked dyskeratosis congenita.
Pearson et al. (2008) reported a 9-month-old Italian boy with HHS. The pregnancy was complicated by decreased fetal movements, intrauterine growth retardation, and oligohydramnios. He had microcephaly, neonatal respiratory distress, and transient thrombocytopenia and leukopenia. At age 4 months, he presented with seizures and axial hypotonia. Brain MRI showed cerebellar hypoplasia, and other radiographs showed distal metaphyseal flaring of the long bones. Although most hematologic indices remained relatively normal, his platelet counts continued to fall below normal, requiring transfusions. He died at age 2 years. Genetic analysis identified a hemizygous mutation in the DKC1 gene (300126.0015).
Female Carriers
Alder et al. (2013) reported 2 unrelated families with DKCX, confirmed by genetic analysis, in which 5 female mutation carriers showed features of the disorder. In the first family, a man developed pulmonary fibrosis at age 46 years, followed by aplastic anemia and myelodysplastic syndrome resulting in death at age 49. His daughter showed graying of the hair at age 20 and wound dehiscence after surgery at age 23. The father's telomere length was below 1% of controls, and the daughter's telomere length was near 5% of controls. X-inactivation in the daughter was skewed at 93%. In the second family, 2 affected brothers had a total of 3 affected daughters. The daughters showed features of DKC in childhood, including skin hyperpigmentation, nail dystrophy, fragile teeth with caries, and hair graying. One daughter had developmental delay and another had anosmia. X-inactivation studies performed in 2 females showed 100% skewing. The findings indicated that mutations in the DKC1 gene can cause telomere-related phenotypes in heterozygous females, and Alder et al. (2013) suggested that heterozygous females should be followed for telomere-related complications, particularly when exposed to environmental insults.
Kalb et al. (1986) described a 33-year-old man with typical features of DKC as well as avascular necrosis of the femoral head. Such had previously been reported in cases of this disorder but only in patients who had received systemic adrenocorticosteroids for pancytopenia or thrombocytopenia.
Reichel et al. (1992) found reports of 15 cases of elevated fetal hemoglobin in association with DKC and added another case, an 11-year-old boy who, in addition to DKC and elevated fetal hemoglobin, had X-linked ocular albinism and juvenile-onset diabetes mellitus.
In fibroblasts from a patient with DKC, DeBauche et al. (1990) found increased frequency of chromatid breaks and chromatid gaps after X-radiation during the G-2 phase of the cell cycle.
Ning et al. (1992) found that the mean number of chromosome breaks per cell in bleomycin-treated lymphocytes was higher in patients with dyskeratosis congenita and in obligatory heterozygotes than in normal individuals. Unequivocal heterozygote detection was not possible owing to overlap of values. In vitro clonogenic assays, as well as long-term bone marrow culture studies (Marsh et al., 1992), suggested that symptoms of aplastic anemia in DKC may be due to a defect at the level of the hematopoietic stem cell.
In 4 patients with DKC, 3 from 1 family and 1 from another, Dokal et al. (1992) found that primary skin fibroblast cultures were abnormal both in morphology (polygonal cell shape, ballooning, and dendritic-like projections) and in growth rate (doubling time about twice normal). Fibroblast survival studies using 4 clastogens and gamma radiation showed no significant difference between DKC and normal fibroblasts. Furthermore, cytogenetic studies performed on peripheral blood lymphocytes showed no difference between DKC and normal lymphocytes with or without prior incubation with clastogens. However, bone marrow metaphases from 1 of 3 patients and fibroblasts from 2 of 4 patients showed numerous unbalanced chromosomal rearrangements (dicentrics, tricentrics, and translocations) in the absence of any clastogenic agents. A higher rate of chromosomal rearrangements was found in the older patients and this, together with the cell-specific differences, appeared to correlate with the clinical evolution of the disease.
In a review, Dokal (1996) noted that late fatal vascular complications had been reported in some cases following bone marrow transplantation (Berthou et al., 1991). This may be related to preexisting endothelial damage in DKC patients, as evidenced by raised von Willebrand factor (613160) levels in the plasma.
Dokal (1996) suggested that DKC may be a good candidate for gene therapy for several reasons: first, it is a single gene disorder; second, the main cause of mortality relates to bone marrow failure and hematopoietic cells are accessible for targeting; and third, hematopoietic stem cells transfected with the normal DKC gene would be expected to have a selective growth advantage in the hypoplastic marrow.
Nobili et al. (2002) summarized the results of hematopoietic stem cell transplantation in 23 DKC patients, only 4 of whom were female, suggesting that most had the X-linked form of the disorder. Allogeneic hematopoietic stem cell transplantation was the only curative approach for the severe bone marrow failure in this disorder. However, results of allograft in these patients had been relatively poor, due to the occurrence of both early and late complications, reflecting the increased sensitivity of endothelial cells to radiotherapy and alkylating agents. Interstitial and obstructive lung disease, as well as liver toxicity, had been observed in DKC patients, leading to the suggestion that radiotherapy and busulfan should be avoided in the conditioning regimens. Nobili et al. (2002) described a 2-year-old boy with DKC who was given cord blood transplantation from an HLA-identical sib, using a fludarabine-based nonmyeloablative conditioning regimen. Improved results were anticipated.
Bryan and Nixon (1965) reported a pedigree with 4 and possibly 5 affected males in a relationship consistent with X-linked recessive inheritance.
Sirinavin and Trowbridge (1975) reported a particularly instructive kindred in which 9 males in 4 sibships and 3 generations were affected.
In the Dyskeratosis Congenita Registry at the Hammersmith Hospital in London, 46 families were recruited (Knight et al., 1998). Of 83 patients, 76 were male, suggesting that the major form of DKC is X-linked.
X-Chromosome Inactivation
Ferraris et al. (1997) hypothesized that, at least in some DKC families, the selective pressure in the heterozygote might be strong enough to determine negative selection of progenitors bearing the mutant allele, resulting in extreme skewing of X-chromosome inactivation in cells of hematopoietic descent. The pattern of methylation of HpaII and HhaI sites with a highly polymorphic CAG repeat in the coding region of the first exon of the androgen receptor gene (AR; 313700) (Allen et al., 1992) was used in these studies. Ferraris et al. (1997) studied 2 families and found that indeed carrier females showed nonrandom X inactivation in whole blood leukocytes, granulocytes, and mononuclear cells.
Using the methylation-sensitive HpaII site in the androgen receptor gene, Vulliamy et al. (1997) found that in 5 different families in which the inheritance of DKC appeared to be X-linked, all 16 carriers showed skewed X-inactivation patterns. The results indicated that in the hematopoiesis of heterozygous females cells expressing the normal allele had a growth advantage over cells that express the mutant allele. In 7 other families with sporadic cases of DKC or with an uncertain pattern of inheritance, both skewed and normal patterns of X inactivation were observed.
In a large kindred with DKC, Sirinavin and Trowbridge (1975) excluded close linkage with the Xg locus. Gutman et al. (1978) observed 2 maternal male cousins. Linkage analysis indicated that dyskeratosis, Xg, and G6PD (305900) are far apart. In an extensively affected kindred, Connor and Teague (1981) excluded close linkage to Xg.
Connor et al. (1986) assigned DKC to chromosome Xq28 by linkage of DNA markers. Its relationships to other loci in this segment were not determined. Arngrimsson et al. (1993) confirmed the linkage with study of 3 further families, which brought the maximum lod score for DKC and DXS52 to 5.33 at zero recombination.
Knight et al. (1996) studied 5 families with additional Xq28 polymorphic markers and concluded that the DKC locus is between GABRA3 (305660) and DXS1108, an interval of approximately 4 Mb.
Devriendt et al. (1997) reported that dyskeratosis congenita was quite clearly X-linked because linkage analysis with markers in the factor VIII gene (F8; 300841) at chromosome Xq28 yielded a lod score of 2.o at a recombination of 0.0, and clinical manifestations of DKC were present in 2 obligate carrier females, e.g., skin lesions following the Blaschko lines. Highly skewed X inactivation was observed in white blood cells, cultured skin fibroblasts, and buccal mucosa from female carriers of DKC in this family. The skewing suggested a critical role for the DKC gene in proliferation of fibroblasts and bone marrow cells. Devriendt et al. (1997) presented photographs of the linear skin lesions of the palmar aspects of the hands.
In patients with X-linked DKC, Heiss et al. (1998) identified 5 different mutations in the DKC1 gene (300126.0001-300126.0005). Three families had previously been reported: Connor et al. (1986) (P40R; 300126.0003); Dokal et al. (1992) (G402Q; 300126.0005); and Devriendt et al. (1997) (F36V; 300126.0001). As a result of large-scale positional cloning and sequencing of the region of Xq28 containing the DKC1 gene, virtually all DKC positional candidates had been identified. By hybridization screening with 28 candidate cDNAs, Heiss et al. (1998) detected a 3-prime deletion in 1 DKC patient with a cDNA probe derived from XAP101. They subsequently identified 5 different missense mutations in 5 unrelated patients in the XAP101 (DKC1) gene. DKC1 is highly conserved across species barriers and is the ortholog of rat NAP57 and S. cerevisiae CBF5. The peptide, referred to as dyskerin, was found to contain 2 TruB pseudouridine synthase motifs, multiple phosphorylation sites, and a carboxy-terminal lysine-rich repeat domain. By analogy to the function of the known dyskerin orthologs, involvement in the cell cycle and nucleolar function was predicted for the protein.
Because of phenotypic similarities between HHS and DKC, Knight et al. (1999) hypothesized that both disorders might be caused by mutation in the same gene. In the family reported by Aalfs et al. (1995) and another family segregating HHS, Knight et al. (1999) identified mutations in the DKC1 gene (300126.0010-300126.0011), demonstrating that HHS is a severe variant of dyskeratosis congenita.
Yaghmai et al. (2000) reported a patient with striking features of both Hoyeraal-Hreidarsson syndrome and DKC who carried an ala353-to-val mutation in the DKC1 gene (300126.0006). Yaghmai et al. (2000) concluded that HHS may be a severe form of DKC in which affected individuals die before characteristic mucocutaneous features develop.
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.
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.
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) (CDKN1B; 600778) and the antiapoptotic factors Bcl-xl (BCL2L1; 600039) and XIAP (300079). Moreover, ribosomes from Dkc1 mutant 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.
Batista et al. (2011) showed that even in the undifferentiated state, induced pluripotent stem cells (iPSCs) from dyskeratosis congenita patients harbor the precise biochemical defects characteristic of each form of the disease and that the magnitude of the telomere maintenance defect in iPSCs correlates with clinical severity. In iPSCs from patients with heterozygous mutations in TERT, the telomerase reverse transcriptase, a 50% reduction in telomerase levels blunts the natural telomere elongation that accompanies reprogramming. In contrast, mutation of dyskerin (DKC1; 300126) in X-linked dyskeratosis congenita severely impairs telomerase activity by blocking telomerase assembly and disrupts telomere elongation during reprogramming. In iPSCs from a form of dyskeratosis congenita caused by mutations in TCAB1 (also known as WRAP53, 612661), telomerase catalytic activity is unperturbed, yet the ability of telomerase to lengthen telomeres is abrogated, since telomerase mislocalizes from Cajal bodies to nucleoli within the iPSCs. Extended culture of DKC1-mutant iPSCs leads to progressive telomere shortening and eventual loss of self-renewal, indicating that a similar process occurs in tissue stem cells in dyskeratosis congenita patients. Their findings in iPSCs from dyskeratosis congenita patients led Batista et al. (2011) to conclude that undifferentiated iPSCs accurately recapitulate features of a human stem cell disease and may serve as a cell culture-based system for the development of targeted therapeutics.
Milgrom et al. (1964) described a black male with dyskeratosis congenita. They pointed out that the 2 serious complications are anemia and cancer, which can develop in the leukoplakia of the anus or mouth or in the skin.
Selmanowitz and van Voolen (1971) pointed out the phenotypic overlap with Fanconi anemia (see 227650) and raised the question whether Fanconi anemia and dyskeratosis congenita might be causally related.
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