Tuesday 18 November 2003
congenital dyskeratosis, Zinsser-Engman-Cole syndrome
Definition: Dyskeratosis congenita (DC) is a rare inherited syndrome characterized by the triad of abnormal skin pigmentation, nail dystrophy, mucosal leucoplakia and bone marrow failure syndrome.
bone marrow hypoplasia with bone marrow failure and pancytopenia (40%)
- bone marrow failure syndrome
- esophageal stenosis
- oral hyperkeratosis in association with lichenoid reaction (16918603)
- visceral cancers
- Hodgkin lymphoma (9729062, 12705757)
- head and neck squamous cell carcinomas (17223904)
There are X-linked, autosomal dominant and autosomal recessive forms of the disease.
The X-linked form is due to mutations in the DKC1 gene at Xq28. The encoded protein, dyskerin, is a component of both small nucleolar ribonuclear protein particles and the telomerase complex. Mutations in DKC1 mainly lead to amino acid substitutions. (9590285)
The autosomal dominant form of the disease is due to mutations in hTR, the RNA component of telomerase (TERC), making it likely that the disease is due to defective telomerase activity. Mutations in hTR are predicted to either disrupt secondary structure or alter the template region.
DKC is a rare inherited multisystem disorder characterized by the triad of reticulated skin pigmentation, nail dystrophy and white patches (leukoplakia) in the mouth. The prevalence is approximately 1 in 1 000 000 individuals, with death occurring at a median age of 16.
Patients typically appear healthy at birth and develop the mucocutaneous features later in life as well as a wide range of somatic abnormalities including bone marrow, pulmonary, gastrointestinal, endocrine, skeletal, urologic, immunologic and neurologic abnormalities.
Bone marrow failure is the leading cause of death, followed by pulmonary disease and cancer.
Almost all the patients in this group develop the mucocutaneous features of the disease during the first two decades of life. Bone marrow failure is especially common and severe. Over 85% of patients have a peripheral cytopenia of at least one lineage and 76% develop pancytopenia at a median age of 10 years. Other families exhibit an autosomal dominant or autosomal recessive pattern of inheritance.
Mutations in genes involved with telomere maintenance have been identified in 40% of clinically diagnosed DKC cases.
A positional cloning approach led to the identification of mutations in the gene DKC1 encoding dyskerin for the X-linked recessive form of the disease.
Dyskerin is a nucleolar protein that copurifies with the RNA component (hTR) and protein component of telomerase (hTERT) in the catalytically active human complex. It is one of four proteins found to be associated with the telomerase complex.
Cell lines from patients with X-linked DKC have reduced levels of hTR that limit telomere length. Affected males have one copy of the X-linked DKC1 gene and their cells express only the mutated form of dyskerin.
Most mutations are missense changes that result in single amino acid substitutions that cluster in two regions, the N-terminal domain and the archaeosine-specific transglycosylase (PUA) domain.
By homology with the crystal structure of a bacterial ortholog of dyskerin, both of these domains are predicted to play a role in binding of hTR.
Several different deletion and nucleotide substitution mutations in the TERC gene, encoding hTR, were first found in patients with the rare autosomal dominant form of DKC.
Many of these mutations affect in vitro hTR accumulation and/or catalytic activity but all demonstrate in vivo telomere length shortening (discussed below).
Subsequently, missense mutations in the gene TERT, encoding the protein component of telomerase, have been described in patients with DKC.
Affected individuals with mutations in either gene (TERC or TERT) have shorter telomere lengths than age-matched controls.
Autosomal dominant inheritance can arise from a dominant negative effect through interaction and inhibition of the wild-type product by the mutated gene product in a multiprotein complex.
Alternatively, autosomal dominant inheritance can arise from haploinsufficiency with a reduction in the normal level of telomerase due to one mutated copy of the gene. In most cases, the effect of the mutations of these two genes appears to be consistent with a mechanism of haploinsufficiency.
Homozygosity mapping of one large consanguineous Saudi Arabian family with autosomal recessive DKC led to the identification of a homozygous missense mutation in NOLA3 (encoding the protein NOP10) that segregated with the phenotype.
This mutation is predicted to result in an arginine to tryptophan substitution (R34W) in a highly conserved region of the protein NOP10, one of four proteins associated with the telomerase complex.
None of the 15 other autosomal recessive families showed linkage to this region and none of the probands (index cases) of 171 uncharacterized DKC families had rare sequence variants in this gene, underscoring the rarity of mutations in this gene as a cause of DKC.
Regardless of the pattern of genetic inheritance, all patients with DKC have very short telomeres, implying a common pathway underlying the mechanism of this disease.
When patients with DKC1 mutations are categorized by disease severity, those with the most severe phenotypes have shorter telomeres than those with the mildest phenotypes (age over 15 years with no co-existent aplastic anemia).
Using the telomere flow-FISH assay and a cut off of total leukocyte telomere lengths below the first percentile, DKC patients could be distinguished from their unaffected relatives with 100% sensitivity and 90% specificity.
Interestingly, DKC families with mutations in either TERC or TERT demonstrate genetic anticipation with a worsening of disease severity and an earlier onset of symptoms with successive generations.
The onset and severity of disease correlates with progressive telomere shortening in later generations. Siblings that do not inherit the mutated TERC gene do not have symptoms.
Even though these siblings inherit short telomeres from the affected parent, the non-mutated telomerase preferentially acts on the shortest telomeres to normalize their lengths.
Thus, DKC patients have to inherit both short telomeres and have a mutation in one of the components of telomerase in order to show anticipation. This is a new mechanism underlying genetic anticipation. Instead of amplification of triplet repeats as is frequently seen in neurodegenerative disorders, in DKC there is a ‘contraction’ of telomere repeats.
Most clinical presentations of DKC are associated with an impaired proliferative capacity of tissues. For example, skin fibroblasts from DKC patients have a longer doubling time and abnormal chromosomal rearrangements in cell culture.
In addition, the number of hematopoietic progenitor cells is decreased in DKC patients (52). The tissues requiring constant renewal, i.e. skin, oral mucosa and bone marrow are the ones that are affected most frequently in DKC.
Connection between sporadic bone marrow failure and dyskeratosis congenita
Over 80% of patients with DKC have bone marrow failure, usually characterized by aplastic anemia or a reduction in all three blood cell lineages.
Because of this, DKC can be considered one of the inherited bone marrow failure syndromes. After mutations in TERC were first described for patients with the rare autosomal dominant form of DKC, it was noted that the clinical phenotypes of mutation carriers were often only bone marrow failure without the mucocutaneous features typical of this disease.
This led to the sequencing of TERC for patients with either the familial or sporadic forms of various bone marrow failure syndromes. Subsequently, different mutations in TERC have been found in patients with aplastic anemia, myelodysplastic syndrome, acute myelogenous leukemia arising from myelodysplastic syndrome, paroxysmal nocturnal hemoglobinuria and essential thrombocytosis.
A similar sequencing strategy led to the identification of mutations in the gene encoding the protein component of telomerase, TERT, in patients with aplastic anemia.
A number of different mutations in both TERC and TERT have been found in patients with bone marrow failure syndromes. Again, most variants in either gene lead to reduced telomerase activity by haploinsufficiency, except for two different mutations in TERC that affect the template domain of hTR and which appear to have a dominant negative effect.
Telomere shortening of circulating leukocytes is observed in many of the different inherited bone marrow failure syndromes. Some patients with these disorders have short telomeres and defined mutations in TERC or TERT, as described above. For others, the connection between accelerated telomere shortening and reduced telomerase activity is not clear.
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