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Pseudouridylation Defect Due to DKC1 and NOP10 Mutations Causes Nephrotic Syndrome with Cataracts, Hearing Impairment, and Enterocolitis

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Pseudouridylation Defect Due to DKC1 and NOP10 Mutations Causes Nephrotic Syndrome with Cataracts, Hearing Impairment, and Enterocolitis Pseudouridylation defect due to DKC1 and NOP10 mutations causes nephrotic syndrome with cataracts, hearing impairment, and enterocolitis Eszter Balogha,b,1, Jennifer C. Chandlerc,1, Máté Vargaa,d,1,2, Mona Tahounc,e,1, Dóra K. Menyhárdf,g, Gusztáv Schaya,h, Tomas Goncalvesi, Renáta Hamard, Regina Légrádia,b, Ákos Szekeresb, Olivier Gribouvalj, Robert Kletak,l, Horia Stanescuk,l, Detlef Bockenhauerk, Andrea Kertia,b, Hywel Williamsm, Veronica Kinslern, Wei-Li Dio, David Curtisp, Maria Kolatsi-Joannouc, Hafsa Hammidc, Anna Szocs} q, Kristóf Perczela,b, Erika Makar, Gergely Toldib, Florentina Savaa, Christelle Arrondelj, Magdolna Kardoss, Attila Finthas, Ahmed Hossaint, Felipe D’Arcou, Mario Kaliakatsosv, Jutta Koeglmeierw, William Mifsudx, Mariya Moosajeey, Ana Faroz, Eszter Jávorszkya,b, Gábor Rudasq, Marwa H. Saiede, Salah Marzouke, Kata Kelenb, Judit Götzeb, George Reuszb, Tivadar Tulassayb, François Dragont,aa, Géraldine Molletj, Susanne Motamenybb, Holger Thielebb,cc, Guillaume Dorvalj, Peter Nürnbergbb,cc, András Perczelf,g, Attila J. Szabób,dd, David A. Longc, Kazunori Tomitai,ee, Corinne Antignacj,ff, Aoife M. Watersc,3,2, and Kálmán Torya,b,3,2 aMTA-SE Lendület Nephrogenetic Laboratory, Semmelweis University, HU 1083 Budapest, Hungary; bFirst Department of Pediatrics, Semmelweis University, HU 1083 Budapest, Hungary; cDevelopmental Biology and Cancer Programme, University College London Great Ormond Street Institute of Child Health, WC1N 1EH London, United Kingdom; dDepartment of Genetics, Eötvös Loránd University, HU 1117 Budapest, Hungary; eClinical and Chemical Pathology Department, Faculty of Medicine Alexandria University, EG 21500, Egypt; fMTA-ELTE Protein Modeling Research Group, Eötvös Loránd University, HU 1117 Budapest, Hungary; gLaboratory of Structural Chemistry and Biology, Eötvös Loránd University, HU 1117 Budapest, Hungary; hDepartment of Biophysics and Radiation Biology, Semmelweis University, HU 1085 Budapest, Hungary; iChromosome Maintenance Research Group, University College London Cancer Institute, WC1E 6DD London, United Kingdom; jLaboratory of Hereditary Kidney Diseases, Imagine Institute, INSERM, UMR 1163, Université de Paris, FR 75015 Paris, France; kDivision of Medicine, Royal Free Hospital, NW3 2QG London, United Kingdom; lNephrology, Faculty of Medical Sciences, University College London, WC1E 6DE London, United Kingdom; mGOSgene, Experimental and Personalised Medicine, University College London Great Ormond Street Institute of Child Health, WC1N 1EH London, United Kingdom; nGenetics and Genomic Medicine, University College London Great Ormond Street Institute of Child Health, WC1N 1EH London, United Kingdom; oInfection, Immunity, Inflammatory, and Physiological Medicine, University College London Great Ormond Street Institute of Child Health, WC1N 1EH London, United Kingdom; pUniversity College London Genetics Institute, University College London, C1E GENETICS 6AD London, United Kingdom; qMedical Imaging Department, Neuroradiology Department, Semmelweis University, HU 1082 Budapest, Hungary; rDepartment of Ophthalmology, Semmelweis University, HU 1085 Budapest, Hungary; sSecond Department of Pathology, Semmelweis University, HU 1091 Budapest, Hungary; tDépartement des Sciences Biologiques, Université du Québec à Montréal, Montréal, QC H2X 1Y4, Canada; uDepartment of Neuro-Radiology, Great Ormond Street Hospital, WC1N 3JH London, United Kingdom; vDepartment of Neurology, Great Ormond Street Hospital, WC1N 3JH London, United Kingdom; wDepartment of Gastroenterology, Great Ormond Street Hospital, WC1N 3JH London, United Kingdom; xDepartment of Histopathology, Great Ormond Street Hospital, WC1N 3JH London, United Kingdom; yInstitute of Ophthalmology, University College London, EC1V 9EL London, United Kingdom; zDivision of Biosciences, Department of Cell and Developmental Biology, University College London, WC1E 6BT London, United Kingdom; aaCentre d’Excellence en Recherche sur les Maladies Orphelines - Fondation Courtois, Université du Québec à Montréal, Montréal, QC H2X 1Y4, Canada; bbCologne Center for Genomics, University of Cologne, DE 50931 Cologne, Germany; ccCenter for Molecular Medicine Cologne, University of Cologne, DE 50931 Cologne, Germany; ddMTA-SE Pediatrics and Nephrology Research Group, HU 1083 Budapest, Hungary; eeDepartment of Life Sciences, Brunel University London, UB8 3PH, United Kingdom; and ffAssistance Publique–Hôpitaux de Paris, Hôpital Necker-Enfants Malades, Service de Génétique Moléculaire, FR 75015 Paris, France Edited by Joan A. Steitz, Howard Hughes Medical Institute and Yale University, New Haven, CT and approved May 4, 2020 (received for review February 18, 2020) RNA modifications play a fundamental role in cellular function. Author contributions: E.B., J.C.C., M.V., M.T., D.K.M., G.S., T.G., R.H., R.L., Á.S., O.G., R.K., Pseudouridylation, the most abundant RNA modification, is cata- H.S., D.B., A.K., H.W., V.K., W.-L.D., D.C., M.K.-J., H.H., K.P., G.T., F.S., C. Arrondel, A.H., ’ lyzed by the H/ACA small ribonucleoprotein (snoRNP) complex F. D Arco, M. Kaliakatsos, J.K., W.M., M.M., A. Faro, E.J., M.H.S., S. Marzouk, G.M., S. Motameny, H.T., D.A.L., K. Tomita, and K. Tory designed research; E.B., J.C.C., M.V., that shares four core proteins, dyskerin (DKC1), NOP10, NHP2, and M.T., D.K.M., G.S., T.G., R.H., R.L., Á.S., O.G., R.K., H.S., D.B., A.K., H.W., V.K., W.-L.D., D.C., GAR1. Mutations in DKC1, NOP10,orNHP2 cause dyskeratosis con- M.K.-J., H.H., K.P., E.M., G.T., F.S., C. Arrondel, M. Kardos, A. Fintha, A.H., F. D’Arco, genita (DC), a disorder characterized by telomere attrition. Here, M. Kaliakatsos, J.K., W.M., M.M., A. Faro, E.J., G. Rudas, M.H.S., S. Marzouk, J.G., G.M., we report a phenotype comprising nephrotic syndrome, cataracts, S. Motameny, H.T., P.N., D.A.L., K. Tomita, and K. Tory performed research; M.V., G.S., Á.S., O.G., D.B., A.S., E.M., M. Kardos, A. Fintha, G. Rudas, T.T., F. Dragon, P.N., A.P., A.J.S., sensorineural deafness, enterocolitis, and early lethality in two D.A.L., K. Tomita, C. Antignac, A.M.W., and K. Tory contributed new reagents/analytic pedigrees: males with DKC1 p.Glu206Lys and two children with tools; E.B., J.C.C., M.V., M.T., D.K.M., G.S., T.G., R.H., R.L., Á.S., O.G., R.K., H.S., D.B., A.K., homozygous NOP10 p.Thr16Met. Females with heterozygous H.W., V.K., W.-L.D., D.C., M.K.-J., H.H., A.S., K.P., E.M., G.T., F.S., M. Kardos, A. Fintha, A.H., ’ DKC1 p.Glu206Lys developed cataracts and sensorineural deaf- F. D Arco, M. Kaliakatsos, J.K., W.M., M.M., A. Faro, E.J., G. Rudas, M.H.S., S. Marzouk, K.K., J.G., G. Reusz, T.T., F. Dragon, G.M., S. Motameny, H.T., G.D., P.N., D.A.L., K. Tomita, ness, but nephrotic syndrome in only one case of skewed C. Antignac, A.M.W., and K. Tory analyzed data; and E.B., J.C.C., M.V., M.T., D.K.M., G.S., X-inactivation. We found telomere attrition in both pedigrees, R.L., Á.S., A.S., E.M., G.T., F. Dragon, P.N., D.A.L., K. Tomita, C. Antignac, A.M.W., and but no mucocutaneous abnormalities suggestive of DC. Both mu- K. Tory wrote the paper. tations fall at the dyskerin–NOP10 binding interface in a region The authors declare no competing interest. distinct from those implicated in DC, impair the dyskerin–NOP10 This article is a PNAS Direct Submission. interaction, and disrupt the catalytic pseudouridylation site. Ac- Published under the PNAS license. cordingly, we found reduced pseudouridine levels in the ribosomal Data deposition: Raw sequence data have been deposited in the Sequence Read Archive, RNA (rRNA) of the patients. Zebrafish dkc1 mutants recapitulate https://www.ncbi.nlm.nih.gov/sra (accession no. PRJNA548449). the human phenotype and show reduced 18S pseudouridylation, 1E.B., J.C.C., M.V., and M.T. contributed equally to this work. ribosomal dysregulation, and a cell-cycle defect in the absence of 2To whom correspondence may be addressed. Email: [email protected], aoife.waters@ telomere attrition. We therefore propose that this human disorder gosh.nhs.uk, or [email protected]. is the consequence of defective snoRNP pseudouridylation and 3A.M.W. and K. Tory contributed equally to this work. ribosomal dysfunction. This article contains supporting information online at https://www.pnas.org/lookup/suppl/ doi:10.1073/pnas.2002328117/-/DCSupplemental. pseudouridylation | H/ACA snoRNP | pediatrics | telomere | rRNA First published June 17, 2020. www.pnas.org/cgi/doi/10.1073/pnas.2002328117 PNAS | June 30, 2020 | vol. 117 | no. 26 | 15137–15147 Downloaded by guest on September 30, 2021 (Family B [FamB]; Fig. 1X). All six affected males in FamA and Significance the two affected females in FamB died in early childhood (Ta- ble 1). To identify the causative genetic loci, we performed linkage Isomerization of uridine to pseudouridine is the most abundant analysis in both families (Fig. 1 W and Y). A single locus of 5.1 Mb RNA modification in eukaryotes. In ribosomal RNA (rRNA), this at the telomeric end of the X chromosome long arm segregated process of pseudouridylation is catalyzed by a ribonucleopro- with the disease in FamA, assuming that the causative mutation tein complex. Mutations of this complex were formerly iden- led to germline mosaicism in I:2. By sequencing the locus-specific tified in mucocutaneous and developmental abnormalities, coding regions of the affected IV:14 and the haploidentical, but resulting from telomere attrition. Here, we identified comple- unaffected, II:9 males, we found a single difference in the se- mentary mutations in two proteins of the complex, affecting quences: a point mutation in DKC1 (c.616 G>A, p.Glu206Lys; SI the highly conserved pseudouridylation catalytic site, associ- Appendix,Fig.S1A). We considered this variant to be causative, as ated with a phenotype characterized by renal, ocular, intestinal, it appeared de novo, segregated with disease in generation II and auditory features, alongside reduced pseudouridine in rRNA corresponding to the assumed maternal germline mosaicism and telomere attrition.
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