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Loss-of-function variants in MYCBP2 cause neurobehavioural phenotypes and corpus callosum defects.
AlAbdi, Lama; Desbois, Muriel; Rusnac, Domnita-Valeria; Sulaiman, Raashda A; Rosenfeld, Jill A; Lalani, Seema; Murdock, David R; Burrage, Lindsay C; Billie Au, Ping Yee; Towner, Shelley; Wilson, William G; Wong, Lawrence; Brunet, Theresa; Strobl-Wildemann, Gertrud; Burton, Jennifer E; Hoganson, George; McWalter, Kirsty; Begtrup, Amber; Zarate, Yuri A; Christensen, Elyse L; Opperman, Karla J; Giles, Andrew C; Helaby, Rana; Kania, Artur; Zheng, Ning; Grill, Brock; Alkuraya, Fowzan S.
Afiliación
  • AlAbdi L; Department of Zoology, College of Science, King Saud University, Riyadh 11362, Saudi Arabia.
  • Desbois M; Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh 11564, Saudi Arabia.
  • Rusnac DV; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA.
  • Sulaiman RA; Department of Pharmacology, University of Washington School of Medicine, Seattle, WA 98195, USA.
  • Rosenfeld JA; Howard Hughes Medical Institute, Department of Pharmacology, University of Washington, Seattle, WA 98195, USA.
  • Lalani S; Department of Medical Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11564, Saudi Arabia.
  • Murdock DR; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • Burrage LC; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • Billie Au PY; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • Wilson WG; Department of Medical Genetics, Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
  • Wong L; Pediatric Genetics, University of Virginia, Charlottesville, VA 22903, USA.
  • Brunet T; Pediatric Genetics, University of Virginia, Charlottesville, VA 22903, USA.
  • Strobl-Wildemann G; Department of Genetics, Northern California Kaiser Permanente, Oakland, CA 94611, USA.
  • Burton JE; Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, 81675 Munich, Germany.
  • Hoganson G; Institute of Neurogenomics (ING), Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany.
  • McWalter K; Department of Human Genetics, MVZ Humangenetik Ulm, 89073 Ulm, Germany.
  • Begtrup A; Department of Genetics, University of Illinois College of Medicine at Peoria, Peoria, IL 61605, USA.
  • Zarate YA; Department of Genetics, University of Illinois College of Medicine at Peoria, Peoria, IL 61605, USA.
  • Christensen EL; Genedx, Inc., 207 Perry Parkway, Gaithersburg, MD 20877, USA.
  • Opperman KJ; Genedx, Inc., 207 Perry Parkway, Gaithersburg, MD 20877, USA.
  • Giles AC; Section of Genetics and Metabolism, Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA.
  • Helaby R; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA.
  • Kania A; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA.
  • Zheng N; Division of Medical Sciences, University of Northern British Columbia, Prince George, BC V2N 4Z9, Canada.
  • Grill B; Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh 11564, Saudi Arabia.
  • Alkuraya FS; Institut de recherches cliniques de Montréal (IRCM), Montréal, QC H2W 1R7, Canada.
Brain ; 146(4): 1373-1387, 2023 04 19.
Article en En | MEDLINE | ID: mdl-36200388
The corpus callosum is a bundle of axon fibres that connects the two hemispheres of the brain. Neurodevelopmental disorders that feature dysgenesis of the corpus callosum as a core phenotype offer a valuable window into pathology derived from abnormal axon development. Here, we describe a cohort of eight patients with a neurodevelopmental disorder characterized by a range of deficits including corpus callosum abnormalities, developmental delay, intellectual disability, epilepsy and autistic features. Each patient harboured a distinct de novo variant in MYCBP2, a gene encoding an atypical really interesting new gene (RING) ubiquitin ligase and signalling hub with evolutionarily conserved functions in axon development. We used CRISPR/Cas9 gene editing to introduce disease-associated variants into conserved residues in the Caenorhabditis elegans MYCBP2 orthologue, RPM-1, and evaluated functional outcomes in vivo. Consistent with variable phenotypes in patients with MYCBP2 variants, C. elegans carrying the corresponding human mutations in rpm-1 displayed axonal and behavioural abnormalities including altered habituation. Furthermore, abnormal axonal accumulation of the autophagy marker LGG-1/LC3 occurred in variants that affect RPM-1 ubiquitin ligase activity. Functional genetic outcomes from anatomical, cell biological and behavioural readouts indicate that MYCBP2 variants are likely to result in loss of function. Collectively, our results from multiple human patients and CRISPR gene editing with an in vivo animal model support a direct link between MYCBP2 and a human neurodevelopmental spectrum disorder that we term, MYCBP2-related developmental delay with corpus callosum defects (MDCD).
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas de Caenorhabditis elegans / Discapacidad Intelectual Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Brain Año: 2023 Tipo del documento: Article País de afiliación: Arabia Saudita Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas de Caenorhabditis elegans / Discapacidad Intelectual Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Brain Año: 2023 Tipo del documento: Article País de afiliación: Arabia Saudita Pais de publicación: Reino Unido