Pathogenic NAP57 mutations decrease ribonucleoprotein assembly in dyskeratosis congenita.

Grozdanov, Petar N.; Fernandez-Fuentes, Narcis; Fiser, Andras; Meier, U. Thomas

X-linked dyskeratosis congenita (DC) is a rare bone marrow failure syndrome caused by mostly missense mutations in the pseudouridine synthase NAP57 (dyskerin/Cbf5). As part of H/ACA ribonucleoproteins (RNPs), NAP57 is important for the biogenesis of ribosomes, spliceosomal small nuclear RNPs, microRNAs and the telomerase RNP. DC mutations concentrate in the N- and C-termini of NAP57 but not in its central catalytic domain raising questions as to their impact. We demonstrate that the N- and C-termini together form the binding surface for the H/ACA RNP assembly factor SHQ1 and that DC mutations modulate the interaction between the two proteins. Pinpointing impaired interaction between NAP57 and SHQ1 as a potential molecular basis for X-linked DC has implications for therapeutic approaches, e.g. by targeting the NAP57–SHQ1 interface with small molecules.

Human Molecular Genetics, 2009, Vol 18, Issue 23, p4546

0964-6906

Academic Journal

10.1093/hmg/ddp416