1. Deficiency of Asparagine Synthetase Causes Congenital Microcephaly and a Progressive Form of Encephalopathy
- Author
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Jacques L. Michaud, Jean-Claude Décarie, Danit Oz-Levi, Mark E. Samuels, Haike Reznik-Wolf, Kimberly Pelak, Yuki Hitomi, Yong-hui Jiang, Grant A. Mitchell, Fadi F. Hamdan, Laurence Colleaux, Xiao-Ping He, Abul Hasnat, Esther Leshinsky-Silver, Yi-Fan Lu, Elizabeth K. Ruzzo, Tally Lerman-Sagie, Sylvia Dobrzeniecka, Xiaodi Yao, Andrea L. Pappas, David Chitayat, Rasesh B. Joshi, David Goldstein, Hanqian Mao, Ramona M. Rodriguiz, Brenda Banwell, William C. Wetsel, Mohammad Safiqul Islam, Tsviya Olender, Jose-Mario Capo-Chichi, Debra L. Silver, Rachel Silver, Doron Lancet, Edna Ben-Asher, James O. McNamara, Lysanne Patry, Bruria Ben-Zeev, Ifat Bar-Joseph, Dorit Lev, Susan Blaser, Dipendra K. Aryal, Guy A. Rouleau, Yair Anikster, Elon Pras, Center of Excellence in Neuroscience of Université de Montréal [Canada], CHU Sainte Justine [Montréal]-Centre de Recherche du CHU Sainte-Justine [Montréal, Canada], University of Toronto, Duke University [Durham], CHU Sainte Justine [Montréal], Institute of Medical Genetics, Wolfson Medical Center, Sheba Medical Center, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Pennsylvania [Philadelphia], Discipline of Computer Science, Faculty of Science and Technology, Queensland University of Technology [Brisbane] (QUT), Laboratoire Hubert Curien [Saint Etienne] (LHC), Institut d'Optique Graduate School (IOGS)-Université Jean Monnet [Saint-Étienne] (UJM)-Centre National de la Recherche Scientifique (CNRS), Montreal Neurological Institute and Hospital, McGill University, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Jean Monnet [Saint-Étienne] (UJM)-Centre National de la Recherche Scientifique (CNRS)-Institut d'Optique Graduate School (IOGS), and McGill University = Université McGill [Montréal, Canada]
- Subjects
Male ,medicine.medical_specialty ,Microcephaly ,Adolescent ,Neuroscience(all) ,Asparagine synthetase ,Encephalopathy ,Mutation, Missense ,Mice, Transgenic ,Biology ,medicine.disease_cause ,Article ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Atrophy ,Intellectual Disability ,Internal medicine ,medicine ,Animals ,Humans ,Missense mutation ,Genetic Predisposition to Disease ,Asparagine ,Child ,030304 developmental biology ,Genetics ,Cerebral atrophy ,0303 health sciences ,Mutation ,General Neuroscience ,Infant, Newborn ,Brain ,Infant ,Aspartate-Ammonia Ligase ,Syndrome ,medicine.disease ,Pedigree ,Endocrinology ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,Female ,030217 neurology & neurosurgery - Abstract
International audience; We analyzed four families that presented with a similar condition characterized by congenital micro-cephaly, intellectual disability, progressive cerebral atrophy, and intractable seizures. We show that recessive mutations in the ASNS gene are responsible for this syndrome. Two of the identified missense mutations dramatically reduce ASNS protein abundance, suggesting that the mutations cause loss of function. Hypomorphic Asns mutant mice have structural brain abnormalities, including enlarged ventricles and reduced cortical thickness, and show deficits in learning and memory mimicking aspects of the patient phenotype. ASNS encodes asparagine synthetase, which catalyzes the synthesis of asparagine from glutamine and aspartate. The neurological impairment resulting from ASNS deficiency may be explained by asparagine depletion in the brain or by accumulation of aspartate/gluta-mate leading to enhanced excitability and neuronal damage. Our study thus indicates that asparagine synthesis is essential for the development and function of the brain but not for that of other organs.
- Published
- 2013