2. Academic Validation
  3. Mutations in MAST1 Cause Mega-Corpus-Callosum Syndrome with Cerebellar Hypoplasia and Cortical Malformations

Mutations in MAST1 Cause Mega-Corpus-Callosum Syndrome with Cerebellar Hypoplasia and Cortical Malformations

  • Neuron. 2018 Dec 19;100(6):1354-1368.e5. doi: 10.1016/j.neuron.2018.10.044.
Ratna Tripathy 1,  Ines Leca 1,  Tessa van Dijk 2,  Janneke Weiss 3,  Bregje W van Bon 4,  Maria Christina Sergaki 1,  Thomas Gstrein 1,  Martin Breuss 5,  Guoling Tian 6,  Nadia Bahi-Buisson 7,  Alexander R Paciorkowski 8,  Alistair T Pagnamenta 9,  Andrea Wenninger-Weinzierl 1,  Maria Fernanda Martinez-Reza 1,  Lukas Landler 1,  Stefano Lise 9,  Jenny C Taylor 9,  Gaetano Terrone 10,  Giuseppina Vitiello 10,  Ennio Del Giudice 10,  Nicola Brunetti-Pierri 11,  Alessandra D'Amico 12,  Alexandre Reymond 13,  Norine Voisin 13,  Jonathan A Bernstein 14,  Ellyn Farrelly 15,  Usha Kini 16,  Thomas A Leonard 17,  Stéphanie Valence 18,  Lydie Burglen 18,  Linlea Armstrong 19,  Susan M Hiatt 20,  Gregory M Cooper 20,  Kimberly A Aldinger 21,  William B Dobyns 21,  Ghayda Mirzaa 21,  Tyler Mark Pierson 22,  Frank Baas 2,  Jamel Chelly 23,  Nicholas J Cowan 6,  David Anthony Keays 24
Affiliations

Affiliations

  • 1 Research Institute of Molecular Pathology, Campus Vienna Biocenter 1, Vienna Biocenter (VBC), Vienna 1030, Austria.
  • 2 Department of Clinical Genetics, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.
  • 3 Amsterdam UMC, Vrije Universiteit Amsterdam, Clinical Genetics, De Boelelaan 1117, Amsterdam, the Netherlands.
  • 4 Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
  • 5 Department of Neurosciences, Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA.
  • 6 Department of Biochemistry & Molecular Pharmacology, NYU Langone Medical Center, New York, NY 10016, USA.
  • 7 Université Paris Descartes, Institut Cochin Hôpital Cochin, 75014 Paris, France.
  • 8 Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA.
  • 9 NIHR Oxford Biomedical Research Centre, Oxford, UK, Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
  • 10 Department of Translational Medical Sciences, Section of Pediatrics, Federico II University, 80131 Naples, Italy.
  • 11 Department of Translational Medical Sciences, Section of Pediatrics, Federico II University, 80131 Naples, Italy; Telethon Institute of Genetics and Medicine, 80078 Pozzuoli, Naples, Italy.
  • 12 Department of Advanced Medical Sciences, University of Naples Federico II, 80131 Naples, Italy.
  • 13 Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland.
  • 14 Stanford School of Medicine, Stanford, CA 94305, USA.
  • 15 Stanford Children's Health, Palo Alto, CA 94304, USA.
  • 16 Department of Clinical Genetics, Oxford Regional Genetics Service, Churchill Hospital, Oxford OX3 7LJ, UK.
  • 17 Center for Medical Biochemistry, Medical University of Vienna, Max F. Perutz Laboratories, Vienna Biocenter (VBC), Campus Vienna Biocenter 5, 1030 Vienna, Austria.
  • 18 Centre de référence des Malformations et Maladies Congénitales du Cervelet et Département de Génétique et Embryologie Médicale, APHP, Hôpital Trousseau, 75012 Paris, France.
  • 19 Provincial Medical Genetics Programme, BCWH and Department of Medical Genetics, University of British Columbia, Vancouver, BC V6H 3N1, Canada.
  • 20 HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.
  • 21 Seattle Children's Research Institute, Center for Integrative Brain Research, Seattle, WA 98101, USA.
  • 22 Departments of Pediatrics and Neurology & the Board of Governors Regenerative Medicine, Institute Cedars Sinai Medical Center, Los Angeles, CA 90048, USA.
  • 23 Service de Diagnostic Génétique, Hôpital Civil de Strasbourg, Hôpitaux Universitaires de Strasbourg, 67091 Strasbourg, France.
  • 24 Research Institute of Molecular Pathology, Campus Vienna Biocenter 1, Vienna Biocenter (VBC), Vienna 1030, Austria. Electronic address: keays@imp.ac.at.
PMID: 30449657 DOI: 10.1016/j.neuron.2018.10.044
Abstract

Corpus callosum malformations are associated with a broad range of neurodevelopmental diseases. We report that de novo mutations in MAST1 cause mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations (MCC-CH-CM) in the absence of megalencephaly. We show that MAST1 is a microtubule-associated protein that is predominantly expressed in post-mitotic neurons and is present in both dendritic and axonal compartments. We further show that Mast1 null Animals are phenotypically normal, whereas the deletion of a single amino acid (L278del) recapitulates the distinct neurological phenotype observed in patients. In Animals harboring Mast1 microdeletions, we find that the PI3K/Akt3/mTOR pathway is unperturbed, whereas Mast2 and Mast3 levels are diminished, indicative of a dominant-negative mode of action. Finally, we report that de novo MAST1 substitutions are present in patients with autism and microcephaly, raising the prospect that mutations in this gene give rise to a spectrum of neurodevelopmental diseases.

Keywords

MAST1; cerebellar hypoplasia; corpus callosum; microdeletion; microtubules.

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