ZFIN ID: ZDB-PUB-200620-13
Pseudouridylation defect due to DKC1 and NOP10 mutations causes nephrotic syndrome with cataracts, hearing impairment, and enterocolitis
Balogh, E., Chandler, J.C., Varga, M., Tahoun, M., Menyhárd, D.K., Schay, G., Goncalves, T., Hamar, R., Légrádi, R., Szekeres, Á., Gribouval, O., Kleta, R., Stanescu, H., Bockenhauer, D., Kerti, A., Williams, H., Kinsler, V., Di, W.L., Curtis, D., Kolatsi-Joannou, M., Hammid, H., Szőcs, A., Perczel, K., Maka, E., Toldi, G., Sava, F., Arrondel, C., Kardos, M., Fintha, A., Hossain, A., D'Arco, F., Kaliakatsos, M., Koeglmeier, J., Mifsud, W., Moosajee, M., Faro, A., Jávorszky, E., Rudas, G., Saied, M.H., Marzouk, S., Kelen, K., Götze, J., Reusz, G., Tulassay, T., Dragon, F., Mollet, G., Motameny, S., Thiele, H., Dorval, G., Nürnberg, P., Perczel, A., Szabó, A.J., Long, D.A., Tomita, K., Antignac, C., Waters, A.M., Tory, K.
Date: 2020
Source: Proceedings of the National Academy of Sciences of the United States of America   117(26): 15137-15147 (Journal)
Registered Authors: Varga, Máté
Keywords: H/ACA snoRNP, pediatrics, pseudouridylation, rRNA, telomere
MeSH Terms:
  • Animals
  • Cataract/genetics*
  • Cell Cycle Proteins/genetics*
  • Child
  • Enterocolitis/genetics*
  • Female
  • Genetic Predisposition to Disease
  • Hearing Loss, Sensorineural/genetics*
  • Humans
  • Longevity
  • Male
  • Models, Molecular
  • Molecular Dynamics Simulation
  • Mutation
  • Nephrotic Syndrome/genetics*
  • Nuclear Proteins/genetics*
  • Pedigree
  • Protein Conformation
  • RNA, Ribosomal/genetics
  • Ribonucleoproteins, Small Nucleolar/genetics*
  • Zebrafish
PubMed: 32554502 Full text @ Proc. Natl. Acad. Sci. USA
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.