NHP2 – Dyskeratosis Congenita

NHP2 encodes a core H/ACA ribonucleoprotein component essential for telomerase RNA (hTR) stability and telomere maintenance. Dyskeratosis congenita (DC) is a rare autosomal recessive telomere biology disorder characterized by mucocutaneous features, bone marrow failure, pulmonary fibrosis, liver cirrhosis, and cancer predisposition (NHP2; Dyskeratosis Congenita).

Several case reports and series describe biallelic NHP2 mutations in DC patients. A compound heterozygous individual carrying c.376G>A (p.Val126Met) and c.460T>A (p.Leu153_Ter154insArgGlyAlaProValAlaProGlyHisLeuProLeuGluAlaIleGlyLeuAlaAlaGlyArgLeuAlaValLeuLeuProThrHisThrAspGlyIlePheProValProGlnGlyThrProSerSerGlnAlaAlaLeuThrAlaLeuSer) presented progressive pancytopenia, pulmonary fibrosis, and cirrhosis over long-term follow-up (PMID:30472699). Homozygous c.415T>C (p.Tyr139His) segregated in two siblings with early-onset developmental delay, cataracts, intellectual disability, nail dystrophy, and hepatic involvement (PMID:40352450). In a multi-patient study, four distinct NHP2 mutations (c.460T>G, c.460T>A, c.415T>C, c.376G>A) were identified in unrelated autosomal recessive DC cases with short telomeres and low hTR levels (PMID:18523010).

Segregation analysis confirms affected siblings in two families (n = 2 affected relatives) with complete cosegregation of homozygous or compound heterozygous NHP2 variants and DC phenotype, consistent with autosomal recessive inheritance.

The variant spectrum comprises missense substitutions (p.Val126Met, p.Tyr139His) and predicted truncating alterations at codon 154 (p.Ter154Arg, p.Ter154Gly) that disrupt H/ACA RNP assembly, with no recurrent or founder alleles reported to date.

Functional studies demonstrate that p.Val126Met and p.Tyr139His impair association of NHP2 with NOP10, causing major defects in pre-RNP assembly with hTR and reduced telomerase RNA levels (PMID:20008900). siRNA knockdown of NHP2 in human cells leads to decreased hTR accumulation, while patient-derived cells show markedly short telomeres, confirming a loss-of-function mechanism (PMID:18523010).

No studies have convincingly refuted the association. The combined genetic and experimental data support a strong gene-disease relationship.

Key Take-home: Autosomal recessive NHP2 variants cause dyskeratosis congenita through impaired H/ACA RNP assembly and telomerase RNA deficiency, guiding molecular diagnosis and management.

References

• Acta haematologica • 2019 • Long-Term Follow-Up of a Case with Dyskeratosis Congenita Caused by NHP2-V126M/X154R Mutation: Genotype-Phenotype Association PMID:30472699
• Molecular syndromology • 2024 • Siblings with a Homozygous Variant in the NHP2 Gene: A Case Report and Review of Literature PMID:40352450
• Proceedings of the National Academy of Sciences of the United States of America • 2008 • Mutations in the telomerase component NHP2 cause the premature ageing syndrome dyskeratosis congenita. PMID:18523010
• Human molecular genetics • 2010 • Effects of dyskeratosis congenita mutations in dyskerin, NHP2 and NOP10 on assembly of H/ACA pre-RNPs. PMID:20008900

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