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Heterozygous loss-of-function variants in DOCK4 cause neurodevelopmental delay and microcephaly.
Herbst, Charlotte; Bothe, Viktoria; Wegler, Meret; Axer-Schaefer, Susanne; Audebert-Bellanger, Séverine; Gecz, Jozef; Cogne, Benjamin; Feldman, Hagit Baris; Horn, Anselm H C; Hurst, Anna C E; Kelly, Melissa A; Kruer, Michael C; Kurolap, Alina; Laquerriere, Annie; Li, Megan; Mark, Paul R; Morawski, Markus; Nizon, Mathilde; Pastinen, Tomi; Polster, Tilman; Saugier-Veber, Pascale; SeSong, Jang; Sticht, Heinrich; Stieler, Jens T; Thifffault, Isabelle; van Eyk, Clare L; Marcorelles, Pascale; Vezain-Mouchard, Myriam; Abou Jamra, Rami; Oppermann, Henry.
Afiliación
  • Herbst C; Institute of Human Genetics, University of Leipzig Medical Center, 04103, Leipzig, Germany.
  • Bothe V; Institute of Human Genetics, University of Leipzig Medical Center, 04103, Leipzig, Germany.
  • Wegler M; Institute of Human Genetics, University of Leipzig Medical Center, 04103, Leipzig, Germany.
  • Axer-Schaefer S; Department of Epileptology, Krankenhaus Mara Bethel Epilepsy Center Medical School OWL, Bielefeld University, Campus Bethel, Bielefeld, Germany.
  • Audebert-Bellanger S; Department of Genetics, CHU Brest, 29000, Brest, France.
  • Gecz J; Adelaide Medical School and Robinson Research Institute, The University of Adelaide, Adelaide, SA, Australia.
  • Cogne B; Service de Génétique Médicale, CHU Nantes, 44000, Nantes, France.
  • Feldman HB; l'institut du Thorax, Nantes Université, CHU Nantes, CNRS, INSERM, 44000, Nantes, France.
  • Horn AHC; The Genetics Institute and Genomics Center, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
  • Hurst ACE; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
  • Kelly MA; Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
  • Kruer MC; Erlangen National High Performance Computing Center, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
  • Kurolap A; Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA.
  • Laquerriere A; HudsonAlpha Clinical Services Lab, HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA.
  • Li M; Barrow Neurological Institute, Phoenix Children's Hospital University of Arizona College of Medicine, Phoenix, USA.
  • Mark PR; The Genetics Institute and Genomics Center, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
  • Morawski M; Department of Anatomy, Inserm U1245 and CHU Rouen, Univ Rouen Normandie, 76000, Rouen, France.
  • Nizon M; Invitae Corp, San Francisco, CA, USA.
  • Pastinen T; Division of Medical Genetics, Helen DeVos Children's Hospital, Corewell Health, Grand Rapids, MI, USA.
  • Polster T; Center of Neuropathology and Brain Research, Medical Faculty, Paul Flechsig Institute, University of Leipzig, Leipzig, Germany.
  • Saugier-Veber P; Service de Génétique Médicale, CHU Nantes, 44000, Nantes, France.
  • SeSong J; l'institut du Thorax, Nantes Université, CHU Nantes, CNRS, INSERM, 44000, Nantes, France.
  • Sticht H; Genomic Medicine Center, Children's Mercy Hospital, Kansas City, USA.
  • Stieler JT; University of Missouri Kansas City School of Medicine, Kansas City, USA.
  • Thifffault I; Department of Epileptology, Krankenhaus Mara Bethel Epilepsy Center Medical School OWL, Bielefeld University, Campus Bethel, Bielefeld, Germany.
  • van Eyk CL; Department of Genetics and Reference Center for Developmental Disorders, Inserm U1245 and CHU Rouen, Univ Rouen Normandie, 76000, Rouen, France.
  • Marcorelles P; Genomic Medicine Institute, Seoul National University, Seoul, Republic of Korea.
  • Vezain-Mouchard M; Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
  • Abou Jamra R; Center of Neuropathology and Brain Research, Medical Faculty, Paul Flechsig Institute, University of Leipzig, Leipzig, Germany.
  • Oppermann H; Genomic Medicine Center, Children's Mercy Hospital, Kansas City, USA.
Hum Genet ; 143(3): 455-469, 2024 Mar.
Article en En | MEDLINE | ID: mdl-38526744
ABSTRACT
Neurons form the basic anatomical and functional structure of the nervous system, and defects in neuronal differentiation or formation of neurites are associated with various psychiatric and neurodevelopmental disorders. Dynamic changes in the cytoskeleton are essential for this process, which is, inter alia, controlled by the dedicator of cytokinesis 4 (DOCK4) through the activation of RAC1. Here, we clinically describe 7 individuals (6 males and one female) with variants in DOCK4 and overlapping phenotype of mild to severe global developmental delay. Additional symptoms include coordination or gait abnormalities, microcephaly, nonspecific brain malformations, hypotonia and seizures. Four individuals carry missense variants (three of them detected de novo) and three individuals carry null variants (two of them maternally inherited). Molecular modeling of the heterozygous missense variants suggests that the majority of them affect the globular structure of DOCK4. In vitro functional expression studies in transfected Neuro-2A cells showed that all missense variants impaired neurite outgrowth. Furthermore, Dock4 knockout Neuro-2A cells also exhibited defects in promoting neurite outgrowth. Our results, including clinical, molecular and functional data, suggest that loss-of-function variants in DOCK4 probable cause a variable spectrum of a novel neurodevelopmental disorder with microcephaly.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Mutación Missense / Proteínas Activadoras de GTPasa / Trastornos del Neurodesarrollo / Heterocigoto / Microcefalia Límite: Adolescent / Animals / Child / Child, preschool / Female / Humans / Infant / Male Idioma: En Revista: Hum Genet Año: 2024 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Alemania
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Mutación Missense / Proteínas Activadoras de GTPasa / Trastornos del Neurodesarrollo / Heterocigoto / Microcefalia Límite: Adolescent / Animals / Child / Child, preschool / Female / Humans / Infant / Male Idioma: En Revista: Hum Genet Año: 2024 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Alemania