2. Academic Validation
  3. Deficiency of asparagine synthetase causes congenital microcephaly and a progressive form of encephalopathy

Deficiency of asparagine synthetase causes congenital microcephaly and a progressive form of encephalopathy

  • Neuron. 2013 Oct 16;80(2):429-41. doi: 10.1016/j.neuron.2013.08.013.
Elizabeth K Ruzzo 1,  José-Mario Capo-Chichi,  Bruria Ben-Zeev,  David Chitayat,  Hanqian Mao,  Andrea L Pappas,  Yuki Hitomi,  Yi-Fan Lu,  Xiaodi Yao,  Fadi F Hamdan,  Kimberly Pelak,  Haike Reznik-Wolf,  Ifat Bar-Joseph,  Danit Oz-Levi,  Dorit Lev,  Tally Lerman-Sagie,  Esther Leshinsky-Silver,  Yair Anikster,  Edna Ben-Asher,  Tsviya Olender,  Laurence Colleaux,  Jean-Claude Décarie,  Susan Blaser,  Brenda Banwell,  Rasesh B Joshi,  Xiao-Ping He,  Lysanne Patry,  Rachel J Silver,  Sylvia Dobrzeniecka,  Mohammad S Islam,  Abul Hasnat,  Mark E Samuels,  Dipendra K Aryal,  Ramona M Rodriguiz,  Yong-Hui Jiang,  William C Wetsel,  James O McNamara,  Guy A Rouleau,  Debra L Silver,  Doron Lancet,  Elon Pras,  Grant A Mitchell,  Jacques L Michaud,  David B Goldstein
Affiliations

Affiliation

  • 1 Center for Human Genome Variation, Duke University School of Medicine, Durham, NC 27708, USA.
PMID: 24139043 DOI: 10.1016/j.neuron.2013.08.013
Abstract

We analyzed four families that presented with a similar condition characterized by congenital microcephaly, 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/glutamate 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.

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