Your browser doesn't support javascript.
loading
THUMPD1 bi-allelic variants cause loss of tRNA acetylation and a syndromic neurodevelopmental disorder.
Broly, Martin; Polevoda, Bogdan V; Awayda, Kamel M; Tong, Ning; Lentini, Jenna; Besnard, Thomas; Deb, Wallid; O'Rourke, Declan; Baptista, Julia; Ellard, Sian; Almannai, Mohammed; Hashem, Mais; Abdulwahab, Ferdous; Shamseldin, Hanan; Al-Tala, Saeed; Alkuraya, Fowzan S; Leon, Alberta; van Loon, Rosa L E; Ferlini, Alessandra; Sanchini, Mariabeatrice; Bigoni, Stefania; Ciorba, Andrea; van Bokhoven, Hans; Iqbal, Zafar; Al-Maawali, Almundher; Al-Murshedi, Fathiya; Ganesh, Anuradha; Al-Mamari, Watfa; Lim, Sze Chern; Pais, Lynn S; Brown, Natasha; Riazuddin, Saima; Bézieau, Stéphane; Fu, Dragony; Isidor, Bertrand; Cogné, Benjamin; O'Connell, Mitchell R.
Afiliación
  • Broly M; Service de Génétique Médicale, CHU de Nantes, 44000 Nantes, France.
  • Polevoda BV; Department of Biochemistry and Biophysics, Center for RNA Biology, University of Rochester, Rochester, NY 14642, USA.
  • Awayda KM; Department of Biochemistry and Biophysics, Center for RNA Biology, University of Rochester, Rochester, NY 14642, USA.
  • Tong N; Department of Biochemistry and Biophysics, Center for RNA Biology, University of Rochester, Rochester, NY 14642, USA.
  • Lentini J; Department of Biology, Center for RNA Biology, University of Rochester, Rochester, NY 14642, USA.
  • Besnard T; Service de Génétique Médicale, CHU de Nantes, 44000 Nantes, France; Université de Nantes, CNRS, INSERM, l'institut du thorax, 44093 Nantes, France.
  • Deb W; Service de Génétique Médicale, CHU de Nantes, 44000 Nantes, France; Université de Nantes, CNRS, INSERM, l'institut du thorax, 44093 Nantes, France.
  • O'Rourke D; Department of Neurology, Children's Health Ireland at Temple Street, Dublin, D01 XD99, Ireland.
  • Baptista J; Exeter Genomics Laboratory, Royal Devon and Exeter NHS Foundation Trust, Exeter EX2 5DW, UK; Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter EX1 2LU, UK.
  • Ellard S; Exeter Genomics Laboratory, Royal Devon and Exeter NHS Foundation Trust, Exeter EX2 5DW, UK; Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter EX1 2LU, UK.
  • Almannai M; Section of Medical Genetics, Children's Hospital, King Fahad Medical City, Riyadh 12231, Saudi Arabia.
  • Hashem M; Department of Translational Genomics, Center for Genomics Medicine, King Faisal Specialist Hospital and Research Center, Riyadh 11564, Saudi Arabia.
  • Abdulwahab F; Department of Translational Genomics, Center for Genomics Medicine, King Faisal Specialist Hospital and Research Center, Riyadh 11564, Saudi Arabia.
  • Shamseldin H; Department of Translational Genomics, Center for Genomics Medicine, King Faisal Specialist Hospital and Research Center, Riyadh 11564, Saudi Arabia.
  • Al-Tala S; Pediatrics Department, Armed Forces Hospital, Khamis Mushait 62413, Saudi Arabia.
  • Alkuraya FS; Department of Translational Genomics, Center for Genomics Medicine, King Faisal Specialist Hospital and Research Center, Riyadh 11564, Saudi Arabia; College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia.
  • Leon A; Research & Innovation (R&I Genetics) Srl, Genetic Laboratory, 35127 Padua, Italy.
  • van Loon RLE; Department of Genetics, University of Utrecht, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands.
  • Ferlini A; Medical Genetics Unit, Department of Medical Sciences, University of Ferrara, Ferrara 44121, Italy.
  • Sanchini M; Medical Genetics Unit, Department of Medical Sciences, University of Ferrara, Ferrara 44121, Italy.
  • Bigoni S; Medical Genetics Unit, Department of Medical Sciences, University of Ferrara, Ferrara 44121, Italy.
  • Ciorba A; ENT & Audiology Unit, Department of Neurosciences, University Hospital of Ferrara, 44124 Cona FE, Italy.
  • van Bokhoven H; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6525 HR Nijmegen, the Netherlands; Department of Human Genetics, Radboud University Medical Center, 6525 HR Nijmegen, the Netherlands.
  • Iqbal Z; Department of Neurology, Oslo University Hospital, 0188 Oslo, Norway.
  • Al-Maawali A; Department of Genetics, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat 123, Oman; Genetic and Developmental Medicine Clinic, Sultan Qaboos University Hospital, Muscat 123, Oman.
  • Al-Murshedi F; Department of Genetics, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat 123, Oman; Genetic and Developmental Medicine Clinic, Sultan Qaboos University Hospital, Muscat 123, Oman.
  • Ganesh A; Department of Ophthalmology, Pediatric Ophthalmology and Ocular Genetics Unit, Sultan Qaboos University Hospital, Muscat 123, Oman.
  • Al-Mamari W; Department of Child Health, Sultan Qaboos University Hospital, Muscat 123, Oman.
  • Lim SC; Victorian Clinical Genetics Services, Parkville, VIC 3052, Australia; Murdoch Children's Research Institute, Parkville, VIC 3052, Australia.
  • Pais LS; Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Brown N; Victorian Clinical Genetics Services, Parkville, VIC 3052, Australia; Murdoch Children's Research Institute, Parkville, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Parkville, VIC 3052, Australia.
  • Riazuddin S; Laboratory of Molecular Genetics, Department of Otorhinolaryngology Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD 21201, USA; Pakistan Institute of Medical Sciences, Shaheed Zulfiqar Ali Bhutto Medical University, Sector G-8/3, Islamabad, Pakistan.
  • Bézieau S; Service de Génétique Médicale, CHU de Nantes, 44000 Nantes, France; Université de Nantes, CNRS, INSERM, l'institut du thorax, 44093 Nantes, France.
  • Fu D; Department of Biology, Center for RNA Biology, University of Rochester, Rochester, NY 14642, USA.
  • Isidor B; Service de Génétique Médicale, CHU de Nantes, 44000 Nantes, France; Université de Nantes, CNRS, INSERM, l'institut du thorax, 44093 Nantes, France.
  • Cogné B; Service de Génétique Médicale, CHU de Nantes, 44000 Nantes, France; Université de Nantes, CNRS, INSERM, l'institut du thorax, 44093 Nantes, France. Electronic address: benjamin.cogne@chu-nantes.fr.
  • O'Connell MR; Department of Biochemistry and Biophysics, Center for RNA Biology, University of Rochester, Rochester, NY 14642, USA. Electronic address: mitchell_oconnell@urmc.rochester.edu.
Am J Hum Genet ; 109(4): 587-600, 2022 04 07.
Article en En | MEDLINE | ID: mdl-35196516
Covalent tRNA modifications play multi-faceted roles in tRNA stability, folding, and recognition, as well as the rate and fidelity of translation, and other cellular processes such as growth, development, and stress responses. Mutations in genes that are known to regulate tRNA modifications lead to a wide array of phenotypes and diseases including numerous cognitive and neurodevelopmental disorders, highlighting the critical role of tRNA modification in human disease. One such gene, THUMPD1, is involved in regulating tRNA N4-acetylcytidine modification (ac4C), and recently was proposed as a candidate gene for autosomal-recessive intellectual disability. Here, we present 13 individuals from 8 families who harbor rare loss-of-function variants in THUMPD1. Common phenotypic findings included global developmental delay, speech delay, moderate to severe intellectual deficiency, behavioral abnormalities such as angry outbursts, facial dysmorphism, and ophthalmological abnormalities. We demonstrate that the bi-allelic variants identified cause loss of function of THUMPD1 and that this defect results in a loss of ac4C modification in small RNAs, and of individually purified tRNA-Ser-CGA. We further corroborate this effect by showing a loss of tRNA acetylation in two CRISPR-Cas9-generated THUMPD1 KO cell lines. In addition, we also show the resultant amino acid substitution that occurs in a missense THUMPD1 allele identified in an individual with compound heterozygous variants results in a marked decrease in THUMPD1 stability and RNA-binding capacity. Taken together, these results suggest that the lack of tRNA acetylation due to THUMPD1 loss of function results in a syndromic form of intellectual disability associated with developmental delay, behavioral abnormalities, hearing loss, and facial dysmorphism.
Asunto(s)
Palabras clave
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas de Unión al ARN / Trastornos del Neurodesarrollo / Discapacidad Intelectual Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Am J Hum Genet Año: 2022 Tipo del documento: Article País de afiliación: Francia Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas de Unión al ARN / Trastornos del Neurodesarrollo / Discapacidad Intelectual Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Am J Hum Genet Año: 2022 Tipo del documento: Article País de afiliación: Francia Pais de publicación: Estados Unidos