Mutations in the telomerase component NHP2 cause the premature ageing syndrome dyskeratosis congenita

• Published in: Proceedings of the National Academy of Sciences - PNAS 2008-06, Vol.105 (23), p.8073-8078
• Main Authors: Vulliamy, Tom, Beswick, Richard, Kirwan, Michael, Marrone, Anna, Digweed, Martin, Walne, Amanda, Dokal, Inderjeet
• Format: Article
• Language: English
• Subjects: Aging; Aging, Premature - genetics; Amino Acid Substitution; Base Sequence; Biological Sciences; Blood; Bone marrow; Cell lines; Cells; DNA Mutational Analysis; Dyskeratosis congenita; Dyskeratosis Congenita - genetics; Female; Genes; Genes, Recessive; Genetic mutation; HeLa Cells; Humans; Male; Molecular Sequence Data; Mutant Proteins - metabolism; Mutation; Mutation - genetics; Nuclear Proteins - chemistry; Nuclear Proteins - genetics; Pedigree; Protein Structure, Secondary; Proteins; Ribonucleic acid; Ribonucleoproteins, Small Nuclear - chemistry; Ribonucleoproteins, Small Nuclear - genetics; Ribonucleoproteins, Small Nucleolar - metabolism; RNA; RNA-Binding Proteins - chemistry; RNA-Binding Proteins - genetics; Small interfering RNA; Small nucleolar ribonucleoproteins; Syndrome; Telomerase - genetics; Telomere - metabolism; Telomeres
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0800042105

Dyskeratosis congenita is a premature aging syndrome characterized by muco-cutaneous features and a range of other abnormalities, including early greying, dental loss, osteoporosis, and malignancy. Dyskeratosis congenita cells age prematurely and have very short telomeres. Patients have mutations in genes that encode components of the telomerase complex (dyskerin, TERC, TERT, and NOP10), important in the maintenance of telomeres. Many dyskeratosis congenita patients remain uncharacterized. Here, we describe the analysis of two other proteins, NHP2 and GAR1, that together with dyskerin and NOP10 are key components of telomerase and small nucleolar ribonucleoprotein (snoRNP) complexes. We have identified previously uncharacterized NHP2 mutations that can cause autosomal recessive dyskeratosis congenita but have not found any GAR1 mutations. Patients with NHP2 mutations, in common with patients bearing dyskerin and NOP10 mutations had short telomeres and low TERC levels. SiRNA-mediated knockdown of NHP2 in human cells led to low TERC levels, but this reduction was not observed after GAR1 knockdown. These findings suggest that, in human cells, GAR1 has a different impact on the accumulation of TERC compared with dyskerin, NOP10, and NHP2. Most of the mutations so far identified in patients with classical dyskeratosis congenita impact either directly or indirectly on the stability of RNAs. In keeping with this effect, patients with dyskerin, NOP10, and now NHP2 mutations have all been shown to have low levels of telomerase RNA in their peripheral blood, providing direct evidence of their role in telomere maintenance in humans.