DKC1 – X-linked Dyskeratosis Congenita

X-linked dyskeratosis congenita (X-DC) is a rare bone marrow failure syndrome characterized by the mucocutaneous triad of reticulate skin pigmentation, nail dystrophy, and oral leukoplakia. It follows an X-linked recessive inheritance pattern and is caused by pathogenic variants in the DKC1 gene, leading to defective dyskerin function and telomere maintenance (Dyskeratosis congenita, X-linked).

Initial case reports described a 2-kb deletion removing the last exon of DKC1 in an affected boy with germline and somatic mosaicism in his mother, who exhibited skewed X-inactivation and transmitted the deletion early in development (PMID:10438713). Subsequent descriptions of X-linked Hoyeraal-Hreidarsson syndrome (a severe infantile variant of X-DC) identified a novel missense variant c.113T>C (p.Ile38Thr) in exon 3 in a Sardinian infant with severe combined immunodeficiency and bone marrow failure (PMID:12437656).

Multi-family studies in Hoyeraal-Hreidarsson syndrome uncovered two novel missense DKC1 mutations in unrelated pedigrees, demonstrating that DKC1 lesions give rise to a wide clinical spectrum including immunodeficiency, microcephaly, cerebellar hypoplasia, and aplastic anemia (PMID:10583221). Additional case series have reported early-onset malignancies in X-DC patients harboring recurrent missense variants such as c.361A>G (p.Ser121Gly), suggesting a predisposition to cancers in young adulthood (PMID:31027506).

The DKC1 variant spectrum includes missense substitutions clustered in exons 3, 4, and 11, rare deletions, and splice mutations. Over 14 unique DKC1 variants have been identified in more than ten unrelated probands, with segregation of pathogenic alleles in affected males and carrier females showing skewed X-inactivation. A representative variant is c.113T>C (p.Ile38Thr), which disrupts dyskerin’s pseudouridine synthase activity.

Functional assays demonstrate that disease-associated dyskerin mutants mislocalize or impair rRNA pseudouridylation without grossly affecting nuclear import, leading to telomere shortening and stem cell failure. Hypomorphic Dkc1 mouse models recapitulate clinical features of DC, including impaired ribosomal RNA modification and late-generation telomere attrition (PMID:12522253). Inhibition of RNA decay pathways rescues hTR levels in DKC1-deficient cells, pointing to therapeutic strategies for restoring telomerase function (PMID:26950371).

Overall, the association between DKC1 and X-linked DC is definitive, supported by multiple unrelated probands, consistent X-linked segregation, and concordant functional data. Genetic testing for DKC1 variants informs diagnosis, carrier detection, and family counseling, while emerging therapies targeting RNA decay offer hope for telomere rescue.

References

• Blood • 1999 • Dyskeratosis congenita caused by a 3' deletion: germline and somatic mosaicism in a female carrier. PMID:10438713
• British journal of haematology • 1999 • Unexplained aplastic anaemia, immunodeficiency, and cerebellar hypoplasia (Hoyeraal-Hreidarsson syndrome) due to mutations in the dyskeratosis congenita gene, DKC1. PMID:10583221
• British journal of haematology • 2002 • A novel DKC1 mutation, severe combined immunodeficiency (T+B-NK- SCID) and bone marrow transplantation in an infant with Hoyeraal-Hreidarsson syndrome. PMID:12437656
• Human mutation • 2013 • Severity of X-linked dyskeratosis congenita (DKCX) cellular defects is not directly related to dyskerin (DKC1) activity in ribosomal RNA biogenesis or mRNA translation. PMID:24115260
• Science • 2003 • Dyskeratosis congenita and cancer in mice deficient in ribosomal RNA modification. PMID:12522253
• Nature structural & molecular biology • 2016 • Inhibition of telomerase RNA decay rescues telomerase deficiency caused by dyskerin or PARN defects. PMID:26950371

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