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Dyskeratosis congenita: a genetic disorder of many faces
Author(s) -
Kirwan M,
Dokal I
Publication year - 2008
Publication title -
clinical genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.543
H-Index - 102
eISSN - 1399-0004
pISSN - 0009-9163
DOI - 10.1111/j.1399-0004.2007.00923.x
Subject(s) - dyskeratosis congenita , telomerase , telomerase rna component , telomere , biology , genetics , ribosome biogenesis , bone marrow failure , cancer research , gene , rna , telomerase reverse transcriptase , ribosome , stem cell , haematopoiesis
Dyskeratosis congenita (DC) is an inherited syndrome exhibiting marked clinical and genetic heterogeneity. It is characterized by multiple features including mucocutaneous abnormalities, bone marrow failure and an increased predisposition to cancer. Three genetic subtypes are recognized: X‐linked recessive DC bears mutations in DKC1 , the gene encoding dyskerin, a component of H/ACA small nucleolar ribonucleoprotein particles; autosomal dominant (AD) DC has heterozygous mutations in either TERC or TERT , the RNA and enzymatic components of telomerase, respectively, and autosomal recessive DC in which the genes involved remain largely elusive. Disease pathology is believed to be a consequence of chromosome instability because of telomerase deficiency due to mutations in DKC1 , TERC and TERT ; in patients with DKC1 mutations, defects in ribosomal RNA modification, ribosome biogenesis, translation control or mRNA splicing may also contribute to disease pathogenesis. The involvement of telomerase complex components in X‐linked and AD forms and the presence of short telomeres in DC patients suggest that DC is primarily a disease of defective telomere maintenance. Treatment is variable and complicated by the development of secondary cancers but, being a monogenic disorder, it could potentially be treated by gene therapy. DC overlaps both clinically and genetically with several other diseases including Hoyeraal–Hreidarsson syndrome, aplastic anaemia and myelodysplasia, among others and its underlying telomeric defect has implications for a broader range of biological processes including ageing and many forms of cancer.