Copenhagen— Researchers have identified a new biallelic mutation in the telomerase component NHP2, which can cause the premature aging syndrome dyskeratosis congenita.
Thomas J. Vulliamy, PhD, MRCPath, from Barts and the London School of Medicine and Dentistry, presented this finding at the 13th Congress of the European Hematology Association.
Dyskeratosis congenita is a genetically heterogeneous, multisystem disorder. The unifying feature of dyskeratosis congenita is that all mutations identified thus far affect molecules involved in telomere maintenance. Defective telomerase leads to premature aging, bone marrow failure, and a predisposition to 32 cancers.
Investigators analyzed the proteins NHP2 and GAR1 using high performance liquid chromatography screening followed by direct DNA sequencing. NHP2 and GAR1 are key components of telomerase, along with dyskerin and NOP10, and small nucleolar ribonucleoprotein (snoRNP) complexes.
Investigators measured telomere lengths by Southern blot analysis and assessed TERC levels and the effects of siRNA knockdown of gene transcripts using quantitative real-time PCR.
Dr Vulliamy and colleagues found that mutations in NHP2 can cause autosomal recessive dyskeratosis congenita. Patients with NHP2, dyskerin, and NOP10 mutations have short telomeres and low TERC levels.
Investigators concluded that this provided direct evidence of their role in telomere maintenance in humans. They did not find any GAR1 mutations, suggesting that GAR1 has a different impact on the accumulation of TERC.
This abstract was chosen as one of the 5 best of the Congress.
