Balogh, Eszter ORCID: 0000-0003-2813-4759, Chandler, Jennifer C. ORCID: 0000-0001-9785-4528, Varga, Mate ORCID: 0000-0003-4289-1705, Tahoun, Mona, Menyhard, Dora K., Schay, Gusztav, Goncalves, Tomas ORCID: 0000-0002-3342-0461, Hamar, Renata, Legradi, Regina ORCID: 0000-0002-5634-4000, Szekeres, Akos, Gribouval, Olivier, Kleta, Robert, Stanescu, Horia, Bockenhauer, Detlef, Kerti, Andrea, Williams, Hywel, Kinsler, Veronica, Di, Wei-Li, Curtis, David, Kolatsi-Joannou, Maria, Hammid, Hafsa, Szocs, Anna, Perczel, Kristof, Maka, Erika, Toldi, Gergely, Sava, Florentina, Arrondel, Christelle, Kardos, Magdolna, Fintha, Attila, Hossain, Ahmed, D'Arco, Felipe, Kaliakatsos, Mario, Koeglmeier, Jutta, Mifsud, William, Moosajee, Mariya, Faro, Ana, Javorszky, Eszter, Rudas, Gabor, Saied, Marwa H., Marzouk, Salah, Kelen, Kata, Gotze, Judit, Reusz, George, Tulassay, Tivadar, Dragon, Francois, Mollet, Geraldine, Motameny, Susanne, Thiele, Holger ORCID: 0000-0002-0169-998X, Dorval, Guillaume ORCID: 0000-0003-3883-1398, Nurnberg, Peter, Perczel, Andras, Szabo, Attila J., Long, David A., Tomita, Kazunori, Antignac, Corinne, Waters, Aoife M. and Tory, Kalman (2020). Pseudouridylation defect due to DKC1 and NOP10 mutations causes nephrotic syndrome with cataracts, hearing impairment, and enterocolitis. Proc. Natl. Acad. Sci. U. S. A., 117 (26). S. 15137 - 15148. WASHINGTON: NATL ACAD SCIENCES. ISSN 0027-8424

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Abstract

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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Balogh, EszterUNSPECIFIEDorcid.org/0000-0003-2813-4759UNSPECIFIED
Chandler, Jennifer C.UNSPECIFIEDorcid.org/0000-0001-9785-4528UNSPECIFIED
Varga, MateUNSPECIFIEDorcid.org/0000-0003-4289-1705UNSPECIFIED
Tahoun, MonaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Menyhard, Dora K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schay, GusztavUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Goncalves, TomasUNSPECIFIEDorcid.org/0000-0002-3342-0461UNSPECIFIED
Hamar, RenataUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Legradi, ReginaUNSPECIFIEDorcid.org/0000-0002-5634-4000UNSPECIFIED
Szekeres, AkosUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gribouval, OlivierUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kleta, RobertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stanescu, HoriaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bockenhauer, DetlefUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kerti, AndreaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Williams, HywelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kinsler, VeronicaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Di, Wei-LiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Curtis, DavidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kolatsi-Joannou, MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hammid, HafsaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Szocs, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Perczel, KristofUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Maka, ErikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Toldi, GergelyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sava, FlorentinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Arrondel, ChristelleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kardos, MagdolnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fintha, AttilaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hossain, AhmedUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
D'Arco, FelipeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kaliakatsos, MarioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koeglmeier, JuttaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mifsud, WilliamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moosajee, MariyaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Faro, AnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Javorszky, EszterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rudas, GaborUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Saied, Marwa H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marzouk, SalahUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kelen, KataUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gotze, JuditUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reusz, GeorgeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tulassay, TivadarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dragon, FrancoisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mollet, GeraldineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Motameny, SusanneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thiele, HolgerUNSPECIFIEDorcid.org/0000-0002-0169-998XUNSPECIFIED
Dorval, GuillaumeUNSPECIFIEDorcid.org/0000-0003-3883-1398UNSPECIFIED
Nurnberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Perczel, AndrasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Szabo, Attila J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Long, David A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tomita, KazunoriUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Antignac, CorinneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Waters, Aoife M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tory, KalmanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-328801
DOI: 10.1073/pnas.2002328117
Journal or Publication Title: Proc. Natl. Acad. Sci. U. S. A.
Volume: 117
Number: 26
Page Range: S. 15137 - 15148
Date: 2020
Publisher: NATL ACAD SCIENCES
Place of Publication: WASHINGTON
ISSN: 0027-8424
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
RECESSIVE DYSKERATOSIS-CONGENITA; RNA; TELOMERASE; GENE; PROTEIN; COMPONENT; DISEASE; COMPLEX; NHP2; ANTICIPATIONMultiple languages
Multidisciplinary SciencesMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/32880

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