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Bi-allelic ATG4D variants are associated with a neurodevelopmental disorder characterized by speech and motor impairment.
Morimoto, Marie; Bhambhani, Vikas; Gazzaz, Nour; Davids, Mariska; Sathiyaseelan, Paalini; Macnamara, Ellen F; Lange, Jennifer; Lehman, Anna; Zerfas, Patricia M; Murphy, Jennifer L; Acosta, Maria T; Wang, Camille; Alderman, Emily; Reichert, Sara; Thurm, Audrey; Adams, David R; Introne, Wendy J; Gorski, Sharon M; Boerkoel, Cornelius F; Gahl, William A; Tifft, Cynthia J; Malicdan, May Christine V.
Afiliación
  • Morimoto M; National Institutes of Health Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, 20892, USA.
  • Bhambhani V; Department of Medical Genetics, Children's Hospitals and Clinics of Minnesota, Minneapolis, MN, 55404, USA.
  • Gazzaz N; Department of Medical Genetics, Faculty of Medicine, University of British Columbia, Vancouver, BC, V6H 3N1, Canada.
  • Davids M; Provincial Medical Genetics Program, British Columbia Women's and Children's Hospital, Vancouver, BC, V6H 3N1, Canada.
  • Sathiyaseelan P; Department of Pediatrics, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.
  • Macnamara EF; National Institutes of Health Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, 20892, USA.
  • Lange J; Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC, V5Z 1L3, Canada.
  • Lehman A; Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, V5A 1S6, Canada.
  • Zerfas PM; National Institutes of Health Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, 20892, USA.
  • Acosta MT; Department of Medical Genetics, Faculty of Medicine, University of British Columbia, Vancouver, BC, V6H 3N1, Canada.
  • Wang C; Diagnostic and Research Services Branch, Office of Research Services, National Institutes of Health, Bethesda, MD, 20892, USA.
  • Alderman E; National Institutes of Health Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, 20892, USA.
  • Reichert S; National Institutes of Health Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, 20892, USA.
  • Thurm A; Department of Medical Genetics, Faculty of Medicine, University of British Columbia, Vancouver, BC, V6H 3N1, Canada.
  • Adams DR; Provincial Medical Genetics Program, British Columbia Women's and Children's Hospital, Vancouver, BC, V6H 3N1, Canada.
  • Gorski SM; Department of Medical Genetics, Children's Hospitals and Clinics of Minnesota, Minneapolis, MN, 55404, USA.
  • Boerkoel CF; Neurodevelopmental and Behavioral Phenotyping Service, Office of the Clinical Director, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, 20892, USA.
  • Gahl WA; National Institutes of Health Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, 20892, USA.
  • Tifft CJ; Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
  • Malicdan MCV; National Institutes of Health Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, 20892, USA.
NPJ Genom Med ; 8(1): 4, 2023 Feb 10.
Article en En | MEDLINE | ID: mdl-36765070
Autophagy regulates the degradation of damaged organelles and protein aggregates, and is critical for neuronal development, homeostasis, and maintenance, yet few neurodevelopmental disorders have been associated with pathogenic variants in genes encoding autophagy-related proteins. We report three individuals from two unrelated families with a neurodevelopmental disorder characterized by speech and motor impairment, and similar facial characteristics. Rare, conserved, bi-allelic variants were identified in ATG4D, encoding one of four ATG4 cysteine proteases important for autophagosome biogenesis, a hallmark of autophagy. Autophagosome biogenesis and induction of autophagy were intact in cells from affected individuals. However, studies evaluating the predominant substrate of ATG4D, GABARAPL1, demonstrated that three of the four ATG4D patient variants functionally impair ATG4D activity. GABARAPL1 is cleaved or "primed" by ATG4D and an in vitro GABARAPL1 priming assay revealed decreased priming activity for three of the four ATG4D variants. Furthermore, a rescue experiment performed in an ATG4 tetra knockout cell line, in which all four ATG4 isoforms were knocked out by gene editing, showed decreased GABARAPL1 priming activity for the two ATG4D missense variants located in the cysteine protease domain required for priming, suggesting that these variants impair the function of ATG4D. The clinical, bioinformatic, and functional data suggest that bi-allelic loss-of-function variants in ATG4D contribute to the pathogenesis of this syndromic neurodevelopmental disorder.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Prognostic_studies / Risk_factors_studies Idioma: En Revista: NPJ Genom Med Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Prognostic_studies / Risk_factors_studies Idioma: En Revista: NPJ Genom Med Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido