DKC1 – Dyskeratosis congenita

Dyskeratosis congenita (DC) is a telomere biology disorder characterized by the mucocutaneous triad of reticular skin hyperpigmentation, nail dystrophy, and oral leukoplakia, with progressive bone marrow failure and heightened cancer risk. The X-linked form of DC is caused by pathogenic variants in DKC1, which encodes the pseudouridine synthase dyskerin, a core component of H/ACA RNPs and telomerase ([PMID:10364516]).

X-linked DC follows an X-linked recessive inheritance pattern, with DKC1 mutations fully segregating with disease in multiple families. In a cohort of 37 families, missense mutations were identified in 21 unrelated pedigrees, including a recurrent hotspot A353V observed in 10 de novo events, confirming multi-family segregation ([PMID:10364516]).

Clinical case series report over 70 affected males across diverse populations. The prototypic mutation c.1058C>T (p.Ala353Val) was first described in a Taiwanese kindred presenting with hyperpigmentation, nail dystrophy, alopecia, leukoplakia, and pancytopenia ([PMID:12513020]). Subsequent reports have expanded the phenotype to include pulmonary fibrosis, immunodeficiency, and enterocolitis, underscoring phenotypic heterogeneity.

The variant spectrum of DKC1 in DC is dominated by missense changes clustering in the PUA domain, with hypomorphic alleles such as c.1156G>A (p.Ala386Thr) and c.1050G>T (p.Met350Ile) associated with milder mucocutaneous phenotypes. Loss-of-function intronic and frameshift alleles (e.g., c.84+7A>G) expand the spectrum to severe early-onset forms.

Functional studies demonstrate that DKC1 mutations impair H/ACA snoRNP assembly, rRNA pseudouridylation, and telomerase RNA (hTR) stability. Dyskerin hypomorphic mice exhibit defective rRNA modification preceding telomere shortening and recapitulate DC features ([PMID:12522253]). Mutant dyskerin reduces hTR levels and telomerase activity, leading to progressive telomere attrition and stem cell exhaustion ([PMID:15240872]).

Therapeutic rescue of telomerase deficiency via inhibition of RNA decay pathways (PAPD5/EXOSC10) restores hTR levels, telomerase activity, and hematopoietic function in DKC1-A353V models, offering a promising targeted strategy ([PMID:26950371]; [PMID:32559291]).

Key take-home: Definitive genetic and functional evidence establishes DKC1 as the causative gene for X-linked DC; early molecular diagnosis enables risk stratification, genetic counselling, and exploration of telomerase-directed therapies.

References

• American Journal of Human Genetics • 1999 • X-linked dyskeratosis congenita is predominantly caused by missense mutations in the DKC1 gene. PMID:10364516
• The Kaohsiung Journal of Medical Sciences • 2002 • DKC1 gene mutation in a Taiwanese kindred with X-linked dyskeratosis congenita. PMID:12513020
• Science • 2003 • Dyskeratosis congenita and cancer in mice deficient in ribosomal RNA modification. PMID:12522253
• Proceedings of the National Academy of Sciences of the United States of America • 2004 • Mouse dyskerin mutations affect accumulation of telomerase RNA and small nucleolar RNA, telomerase activity, and ribosomal RNA processing. PMID:15240872
• Nature Structural & Molecular Biology • 2016 • Inhibition of telomerase RNA decay rescues telomerase deficiency caused by dyskerin or PARN defects. PMID:26950371
• Blood Advances • 2020 • Chemical inhibition of PAPD5/7 rescues telomerase function and hematopoiesis in dyskeratosis congenita. PMID:32559291

Evidence Based Scoring (AI generated)