NOP10 – Dyskeratosis Congenita

NOP10 encodes a core H/ACA small nucleolar ribonucleoprotein component essential for telomerase RNA maturation and telomere maintenance. It is one of eight genes implicated in Dyskeratosis Congenita, with panel‐based screening identifying NOP10 among genes evaluated in two unrelated patients presenting the classical DC triad (n=2) (PMID:27182588). However, specific NOP10 variants have not been systematically reported in these clinical series, and familial segregation data are lacking, limiting direct genotype–phenotype correlation. No additional probands with biallelic NOP10 variants have been published in multi-patient cohorts, and segregation of candidate variants in DC kindreds remains unreported. Consequently, genetic evidence for the NOP10–DC association is currently limited.

Functional assays provide moderate support: the NOP10 c.100C>T (p.Arg34Trp) mutation, identified in a DC context, severely impairs pre-RNP assembly with the H/ACA domain of telomerase RNA, consistent with a loss-of-function mechanism (PMID:20008900). Additional mechanistic studies reinforce that NOP10 is critical for telomerase RNA stability and H/ACA RNP formation. In contrast, a homozygous NOP10 c.47C>T (p.Thr16Met) allele causes a distinct ribosomopathy lacking mucocutaneous DC features, highlighting allelic heterogeneity and phenotype spectrum (PMID:32554502). No studies to date have reported segregation of NOP10 variants with DC, and no genotype‐driven animal models are available. Integration of genetic and functional data yields a ClinGen clinical validity classification of Limited due to minimal proband‐level genetic evidence balanced by mechanistic plausibility. Key take‐home: NOP10 is a plausible DC gene warranting inclusion in extended telomere biology panels, but variant interpretation requires caution given the current paucity of genetic data.

References

• Ethiopian medical journal • 2015 • DYSKERATOSIS CONGENITA IN TWO ETHIOPIAN BROTHERS. PMID:27182588
• Human molecular genetics • 2010 • Effects of dyskeratosis congenita mutations in dyskerin, NHP2 and NOP10 on assembly of H/ACA pre-RNPs. PMID:20008900
• Proceedings of the National Academy of Sciences of the United States of America • 2020 • Pseudouridylation defect due to DKC1 and NOP10 mutations causes nephrotic syndrome with cataracts, hearing impairment, and enterocolitis. PMID:32554502

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