例如:"lncRNA", "apoptosis", "WRKY"

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

Proc Natl Acad Sci U S A. 2020 Jun 30;117(26):15137-15147. Epub 2020 Jun 17
Eszter Balogh 1 , Jennifer C Chandler 2 , Máté Varga 3 , Mona Tahoun 4 , Dóra K Menyhárd 5 , Gusztáv Schay 6 , Tomas Goncalves 7 , Renáta Hamar 3 , Regina Légrádi 1 , Ákos Szekeres 1 , Olivier Gribouval 8 , Robert Kleta 9 , Horia Stanescu 9 , Detlef Bockenhauer 10 , Andrea Kerti 1 , Hywel Williams 11 , Veronica Kinsler 12 , Wei-Li Di 13 , David Curtis 14 , Maria Kolatsi-Joannou 2 , Hafsa Hammid 2 , Anna Szőcs 15 , Kristóf Perczel 1 , Erika Maka 16 , Gergely Toldi 1 , Florentina Sava 17 , Christelle Arrondel 8 , Magdolna Kardos 18 , Attila Fintha 18 , Ahmed Hossain 19 , Felipe D'Arco 20 , Mario Kaliakatsos 21 , Jutta Koeglmeier 22 , William Mifsud 23 , Mariya Moosajee 24 , Ana Faro 25 , Eszter Jávorszky 1 , Gábor Rudas 15 , Marwa H Saied 4 , Salah Marzouk 4 , Kata Kelen 1 , Judit Götze 1 , George Reusz 1 , Tivadar Tulassay 1 , François Dragon 26 , Géraldine Mollet 8 , Susanne Motameny 27 , Holger Thiele 28 , Guillaume Dorval 8 , Peter Nürnberg 28 , András Perczel 5 , Attila J Szabó 29 , David A Long 2 , Kazunori Tomita 30 , Corinne Antignac 31 , Aoife M Waters 32 , Kálmán Tory 1
Eszter Balogh 1 , Jennifer C Chandler 2 , Máté Varga 3 , Mona Tahoun 4 , Dóra K Menyhárd 5 , Gusztáv Schay 6 , Tomas Goncalves 7 , Renáta Hamar 3 , Regina Légrádi 1 , Ákos Szekeres 1 , Olivier Gribouval 8 , Robert Kleta 9 , Horia Stanescu 9 , Detlef Bockenhauer 10 , Andrea Kerti 1 , Hywel Williams 11 , Veronica Kinsler 12 , Wei-Li Di 13 , David Curtis 14 , Maria Kolatsi-Joannou 2 , Hafsa Hammid 2 , Anna Szőcs 15 , Kristóf Perczel 1 , Erika Maka 16 , Gergely Toldi 1 , Florentina Sava 17 , Christelle Arrondel 8 , Magdolna Kardos 18 , Attila Fintha 18 , Ahmed Hossain 19 , Felipe D'Arco 20 , Mario Kaliakatsos 21 , Jutta Koeglmeier 22 , William Mifsud 23 , Mariya Moosajee 24 , Ana Faro 25 , Eszter Jávorszky 1 , Gábor Rudas 15 , Marwa H Saied 4 , Salah Marzouk 4 , Kata Kelen 1 , Judit Götze 1 , George Reusz 1 , Tivadar Tulassay 1 , François Dragon 26 , Géraldine Mollet 8 , Susanne Motameny 27 , Holger Thiele 28 , Guillaume Dorval 8 , Peter Nürnberg 28 , András Perczel 5 , Attila J Szabó 29 , David A Long 2 , Kazunori Tomita 30 , Corinne Antignac 31 , Aoife M Waters 32 , Kálmán Tory 1
+ et al

[No authors listed]

Author information
  • 1 First Department of Pediatrics, Semmelweis University, HU 1083 Budapest, Hungary.
  • 2 Developmental Biology and Cancer Programme, University College London Great Ormond Street Institute of Child Health, WC1N 1EH London, United Kingdom.
  • 3 Department of Genetics, Eötvös Loránd University, HU 1117 Budapest, Hungary.
  • 4 Clinical and Chemical Pathology Department, Faculty of Medicine Alexandria University, EG 21500, Egypt.
  • 5 Laboratory of Structural Chemistry and Biology, Eötvös Loránd University, HU 1117 Budapest, Hungary.
  • 6 Department of Biophysics and Radiation Biology, Semmelweis University, HU 1085 Budapest, Hungary.
  • 7 Chromosome Maintenance Research Group, University College London Cancer Institute, WC1E 6DD London, United Kingdom.
  • 8 Laboratory of Hereditary Kidney Diseases, Imagine Institute, INSERM, UMR 1163, Université de Paris, FR 75015 Paris, France.
  • 9 Nephrology, Faculty of Medical Sciences, University College London, WC1E 6DE London, United Kingdom.
  • 10 Division of Medicine, Royal Free Hospital, NW3 2QG London, United Kingdom.
  • 11 GOSgene, Experimental and Personalised Medicine, University College London Great Ormond Street Institute of Child Health, WC1N 1EH London, United Kingdom.
  • 12 Genetics and Genomic Medicine, University College London Great Ormond Street Institute of Child Health, WC1N 1EH London, United Kingdom.
  • 13 Infection, Immunity, Inflammatory, and Physiological Medicine, University College London Great Ormond Street Institute of Child Health, WC1N 1EH London, United Kingdom.
  • 14 University College London Genetics Institute, University College London, C1E 6AD London, United Kingdom.
  • 15 Medical Imaging Department, Neuroradiology Department, Semmelweis University, HU 1082 Budapest, Hungary.
  • 16 Department of Ophthalmology, Semmelweis University, HU 1085 Budapest, Hungary.
  • 17 MTA-SE Lendület Nephrogenetic Laboratory, Semmelweis University, HU 1083 Budapest, Hungary.
  • 18 Second Department of Pathology, Semmelweis University, HU 1091 Budapest, Hungary.
  • 19 Département des Sciences Biologiques, Université du Québec à Montréal, Montréal, QC H2X 1Y4, Canada.
  • 20 Department of Neuro-Radiology, Great Ormond Street Hospital, WC1N 3JH London, United Kingdom.
  • 21 Department of Neurology, Great Ormond Street Hospital, WC1N 3JH London, United Kingdom.
  • 22 Department of Gastroenterology, Great Ormond Street Hospital, WC1N 3JH London, United Kingdom.
  • 23 Department of Histopathology, Great Ormond Street Hospital, WC1N 3JH London, United Kingdom.
  • 24 Institute of Ophthalmology, University College London, EC1V 9EL London, United Kingdom.
  • 25 Division of Biosciences, Department of Cell and Developmental Biology, University College London, WC1E 6BT London, United Kingdom.
  • 26 Centre d'Excellence en Recherche sur les Maladies Orphelines - Fondation Courtois, Université du Québec à Montréal, Montréal, QC H2X 1Y4, Canada.
  • 27 Cologne Center for Genomics, University of Cologne, DE 50931 Cologne, Germany.
  • 28 Center for Molecular Medicine Cologne, University of Cologne, DE 50931 Cologne, Germany.
  • 29 MTA-SE Pediatrics and Nephrology Research Group, HU 1083 Budapest, Hungary.
  • 30 Department of Life Sciences, Brunel University London, UB8 3PH, United Kingdom.
  • 31 Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades, Service de Génétique Moléculaire, FR 75015 Paris, France.
  • 32 Developmental Biology and Cancer Programme, University College London Great Ormond Street Institute of Child Health, WC1N 1EH London, United Kingdom; mvarga@ttk.elte.hu aoife.waters@gosh.nhs.uk tory.kalman@med.semmelweis-univ.hu.

摘要


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.

KEYWORDS: H/ACA snoRNP, pediatrics, pseudouridylation, rRNA, telomere