Fiche publication
Date publication
avril 2020
Journal
Human molecular genetics
Auteurs
Membres identifiés du Cancéropôle Est :
Dr MARCAIS Ambroise
Tous les auteurs :
Benyelles M, O'Donohue MF, Kermasson L, Lainey E, Borie R, Lagresle-Peyrou C, Nunes H, Cazelles C, Fourrage C, Ollivier E, Marcais A, Gamez AS, Morice-Picard F, Caillaud D, Pottier N, Ménard C, Ba I, Fernandes A, Crestani B, de Villartay JP, Gleizes PE, Callebaut I, Kannengiesser C, Revy P
Lien Pubmed
Résumé
Telomeres are nucleoprotein structures at the end of chromosomes. The telomerase complex, constituted of the catalytic subunit TERT, the RNA matrix hTR and several cofactors, including the H/ACA box ribonucleoproteins Dyskerin, NOP10, GAR1, NAF1 and NHP2, regulates telomere length. In humans, inherited defects in telomere length maintenance are responsible for a wide spectrum of clinical premature aging manifestations including pulmonary fibrosis (PF), dyskeratosis congenita (DC), bone marrow failure and predisposition to cancer. NHP2 mutations have been so far reported only in two patients with DC. Here, we report the first case of Høyeraal-Hreidarsson syndrome, the severe form of DC, caused by biallelic missense mutations in NHP2. Additionally, we identified three unrelated patients with PF carrying NHP2 heterozygous mutations. Strikingly, one of these patients acquired a somatic mutation in the promoter of TERT that likely conferred a selective advantage in a subset of blood cells. Finally, we demonstrate that a functional deficit of human NHP2 affects ribosomal RNA biogenesis. Together, our results broaden the functional consequences and clinical spectrum of NHP2 deficiency.
Mots clés
Aged, Amino Acid Sequence, Dyskeratosis Congenita, etiology, Female, Fetal Growth Retardation, etiology, Humans, Infant, Newborn, Intellectual Disability, etiology, Male, Microcephaly, etiology, Middle Aged, Mutation, Nuclear Proteins, chemistry, Pedigree, Promoter Regions, Genetic, Pulmonary Fibrosis, etiology, RNA, Ribosomal, biosynthesis, Ribonucleoproteins, Small Nuclear, chemistry, Sequence Homology, Telomerase, genetics, Transcription, Genetic
Référence
Hum Mol Genet. 2020 04 15;29(6):907-922
