Alternative titles; symbols
HGNC Approved Gene Symbol: NHP2
Cytogenetic location: 5q35.3 Genomic coordinates (GRCh38) : 5:178,149,463-178,153,885 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q35.3 | Dyskeratosis congenita, autosomal recessive 2 | 613987 | Autosomal recessive | 3 |
By searching an EST database for orthologs of yeast Nhp2, followed by 5-prime and 3-prime RACE, Pogacic et al. (2000) obtained a cDNA encoding NPH2. The deduced 153-amino acid protein is 55% identical to the yeast protein. Complementation analysis showed that the recombinant human protein can replace the yeast protein.
Gross (2021) mapped the NHP2 gene to chromosome 5q35.3 based on an alignment of the NHP2 sequence (GenBank BC006387) with the genomic sequence (GRCh38).
By immunoprecipitation and Western blot analysis, Pogacic et al. (2000) showed that NPH2 associates with NOP10 (606471), dyskerin (DKC1; 300126), and GAR1 (606468) in structures corresponding to H/ACA snoRNPs, but not to C/D snoRNPs, and to telomerase. SnoRNPs of the H/ACA class specify the sites of uridine-to-pseudouridine conversion (See Tollervey and Kiss, 1997). Immunofluorescence microscopy demonstrated colocalization of NPH2 with GAR1, NOP10, and DKC1, but not with fibrillarin (FBL; 134795), in nucleolar dense fibrillar components and in Cajal bodies (also called coiled bodies; see 600272). Pogacic et al. (2000) concluded that NPH2 is likely to be a primary RNA-binding protein.
In 2 unrelated Turkish patients with autosomal recessive dyskeratosis congenita-2 (DKCB2; 613987), Vulliamy et al. (2008) identified biallelic mutations in the NPH2 gene (606470.0001-606470.0003). Both patients had shortened telomeres and decreased serum TERC (602322) RNA. The 2 patients were identified from a larger group of 117 patients with the disorder; no other pathogenic NPH2 variants and no mutations in the GAR1 gene were identified.
In a 22-year-old Turkish man with autosomal recessive dyskeratosis congenita-2 (DKCB2; 613987), Vulliamy et al. (2008) identified a homozygous 415T-C transition in the NPH2 gene, resulting in a tyr139-to-his (Y139H) substitution. The patient had nail dystrophy, thrombocytopenia, testicular atrophy, opportunistic infections, growth and mental retardation, liver cirrhosis, and intracranial calcification. His parents, who were not related, were asymptomatic and heterozygous for the mutation. The patient had shortened telomeres and decreased levels of serum TERC (602322) RNA. Functional expression studies in HeLa cells showed that TERC levels were increased when wildtype NPH2 was expressed in cells containing the mutant NPH2.
In a 12-year-old Turkish boy with autosomal recessive dyskeratosis congenita-2 (DKCB2; 613987), Vulliamy et al. (2008) identified compound heterozygosity for 2 mutations in the NPH2 gene: a 376G-A transition resulting in a val126-to-met (V126M) substitution, and a 460T-A transversion resulting in ter154-to-arg (X154R; 606470.0003). The X154R substitution is predicted to result in an elongated protein with 51 residues added to the C terminus. The patient had the classical mucocutaneous triad of nail dystrophy, leucoplakia, and reticulate skin pigmentation. He developed peripheral pancytopenia because of progressive bone marrow failure; no other somatic abnormalities were reported. Both unaffected parents were heterozygous for 1 of the mutations. The patient had shortened telomeres and decreased levels of serum TERC (602322) RNA.
For discussion of the 460T-A transversion in the NPH2 gene, resulting in a ter154-to-arg (X154R) substitution, that was found in compound heterozygous state in a Turkish boy with autosomal recessive dyskeratosis congenita-2 (DKCB2; 613987) by Vulliamy et al. (2008), see 606470.0002.
Gross, M. B. Personal Communication. Baltimore, Md. 11/1/2021.
Pogacic, V., Dragon, F., Filipowicz, W. Human H/ACA small nucleolar RNPs and telomerase share evolutionarily conserved proteins NHP2 and NOP10. Molec. Cell. Biol. 20: 9028-9040, 2000. [PubMed: 11074001] [Full Text: https://doi.org/10.1128/MCB.20.23.9028-9040.2000]
Tollervey, D., Kiss, T. Function and synthesis of small nucleolar RNAs. Curr. Opin. Cell Biol. 9: 337-342, 1997. [PubMed: 9159079] [Full Text: https://doi.org/10.1016/s0955-0674(97)80005-1]
Vulliamy, T., Beswick, R., Kirwan, M., Marrone, A., Digweed, M., Walne, A., Dokal, I. Mutations in the telomerase component NHP2 cause the premature ageing syndrome dyskeratosis congenita. Proc. Nat. Acad. Sci. 105: 8073-8078, 2008. [PubMed: 18523010] [Full Text: https://doi.org/10.1073/pnas.0800042105]