Pseudouridylation defect due to DKC1 and NOP10 mutations causes nephrotic syndrome with cataracts, hearing impairment, and enterocolitis

• DOI: 10.1073/pnas.2002328117
• Publication Date: 2020-06-17T23:55:19Z
• Authors: Eszter Balogh; Jennifer C. Chandler; Máté Varga; Mona Tahoun; Dóra K. Menyhárd; Gusztáv Schay; Tomas Goncalves; Renáta Hamar; Regina Légrádi; Ákos Szekeres; Olivier Gribouval; Robert Kleta; Horia Stanescu; Detlef Bockenhauer; Andrea Kerti; Hywel Williams; Veronica Kinsler; Wei-Li Di; David Curtis; Maria Kolatsi-Joa...; Hafsa Hammid; Anna Szőcs; Kristóf Perczel; Erika Maka; Gergely Toldi; Florentina Sava; Christelle Arrondel; Magdolna Kardos; Attila Fintha; Ahmed Hossain; Felipe D’Arco; Mario Kaliakatsos; Jutta Koeglmeier; William Mifsud; Mariya Moosajee; Ana Faro; Eszter Jávorszky; Gábor Rudas; Marwa H. Saied; Salah Marzouk; Kata Kelen; Judit Götze; George Reusz; Tivadar Tulassay; François Dragon; Géraldine Mollet; Susanne Motameny; Holger Thiele; Guillaume Dorval; Peter Nürnberg; András Perczel; Attila J. Szabó; David A. Long; Kazunori Tomita; Corinne Antignac; Aoife M. Waters; Kálmán Tory
• Keywords: Male; Models, Molecular; Nephrotic Syndrome; pediatrics; Protein Conformation; Hearing Loss, Sensorineural; Longevity; 610; Cell Cycle Proteins; Molecular Dynamics Simulation; Pediatrics; Cataract; 03 medical and health sciences; Ribonucleoproteins, Small Nucleolar; Animals; Humans; Pseudouridylation; Genetic Predisposition to Disease; rRNA; Child; telomere; 0303 health sciences; Enterocolitis; Nuclear Proteins; Pedigree; 3. Good health; Telomerer; RNA, Ribosomal; pseudouridylation; H/ACA snoRNP; Mutation; RNA; Female

RNA modifications play a fundamental role in cellular function. Pseudouridylation, the most abundant RNA modification, is catalyzed by the H/ACA small ribonucleoprotein (snoRNP) complex that shares four core proteins, dyskerin (DKC1), NOP10, NHP2, and GAR1. Mutations in DKC1 , NOP10 , or NHP2 cause dyskeratosis congenita (DC), a disorder characterized by telomere attrition. Here, we report a phenotype comprising nephrotic syndrome, cataracts, sensorineural deafness, enterocolitis, and early lethality in two pedigrees: males with DKC1 p.Glu206Lys and two children with homozygous NOP10 p.Thr16Met. Females with heterozygous DKC1 p.Glu206Lys developed cataracts and sensorineural deafness, but nephrotic syndrome in only one case of skewed X-inactivation. We found telomere attrition in both pedigrees, but no mucocutaneous abnormalities suggestive of DC. Both mutations fall at the dyskerin–NOP10 binding interface in a region distinct from those implicated in DC, impair the dyskerin–NOP10 interaction, and disrupt the catalytic pseudouridylation site. Accordingly, we found reduced pseudouridine levels in the ribosomal RNA (rRNA) of the patients. Zebrafish dkc1 mutants recapitulate the human phenotype and show reduced 18S pseudouridylation, ribosomal dysregulation, and a cell-cycle defect in the absence of telomere attrition. We therefore propose that this human disorder is the consequence of defective snoRNP pseudouridylation and ribosomal dysfunction.