title: Deficiency of asparagine synthetase causes congenital microcephaly and a progressive form of encephalopathy.
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.
authors.affiliation: Center for Human Genome Variation, Duke University School of Medicine, Durham, NC 27708, USA.
authors.forename: Elizabeth K
authors.initials: EK
authors.lastname: Ruzzo
authors.forename: José-Mario
authors.initials: JM
authors.lastname: Capo-Chichi
authors.forename: Bruria
authors.initials: B
authors.lastname: Ben-Zeev
authors.forename: David
authors.initials: D
authors.lastname: Chitayat
authors.forename: Hanqian
authors.initials: H
authors.lastname: Mao
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Pappas
authors.forename: Yuki
authors.initials: Y
authors.lastname: Hitomi
authors.forename: Yi-Fan
authors.initials: YF
authors.lastname: Lu
authors.forename: Xiaodi
authors.initials: X
authors.lastname: Yao
authors.forename: Fadi F
authors.initials: FF
authors.lastname: Hamdan
authors.forename: Kimberly
authors.initials: K
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authors.forename: Haike
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authors.lastname: Reznik-Wolf
authors.forename: Ifat
authors.initials: I
authors.lastname: Bar-Joseph
authors.forename: Danit
authors.initials: D
authors.lastname: Oz-Levi
authors.forename: Dorit
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authors.lastname: Lev
authors.forename: Tally
authors.initials: T
authors.lastname: Lerman-Sagie
authors.forename: Esther
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authors.lastname: Leshinsky-Silver
authors.forename: Yair
authors.initials: Y
authors.lastname: Anikster
authors.forename: Edna
authors.initials: E
authors.lastname: Ben-Asher
authors.forename: Tsviya
authors.initials: T
authors.lastname: Olender
authors.forename: Laurence
authors.initials: L
authors.lastname: Colleaux
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Décarie
authors.forename: Susan
authors.initials: S
authors.lastname: Blaser
authors.forename: Brenda
authors.initials: B
authors.lastname: Banwell
authors.forename: Rasesh B
authors.initials: RB
authors.lastname: Joshi
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: He
authors.forename: Lysanne
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authors.lastname: Patry
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Silver
authors.forename: Sylvia
authors.initials: S
authors.lastname: Dobrzeniecka
authors.forename: Mohammad S
authors.initials: MS
authors.lastname: Islam
authors.forename: Abul
authors.initials: A
authors.lastname: Hasnat
authors.forename: Mark E
authors.initials: ME
authors.lastname: Samuels
authors.forename: Dipendra K
authors.initials: DK
authors.lastname: Aryal
authors.forename: Ramona M
authors.initials: RM
authors.lastname: Rodriguiz
authors.forename: Yong-Hui
authors.initials: YH
authors.lastname: Jiang
authors.forename: William C
authors.initials: WC
authors.lastname: Wetsel
authors.forename: James O
authors.initials: JO
authors.lastname: McNamara
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rouleau
authors.forename: Debra L
authors.initials: DL
authors.lastname: Silver
authors.forename: Doron
authors.initials: D
authors.lastname: Lancet
authors.forename: Elon
authors.initials: E
authors.lastname: Pras
authors.forename: Grant A
authors.initials: GA
authors.lastname: Mitchell
authors.forename: Jacques L
authors.initials: JL
authors.lastname: Michaud
authors.forename: David B
authors.initials: DB
authors.lastname: Goldstein
mesh_terms: D000293:Adolescent; D000818:Animals; D001217:Aspartate-Ammonia Ligase / Q000172:deficiency* / Q000235:genetics*; D001284:Atrophy / Q000150:complications / Q000201:enzymology / Q000235:genetics; D001921:Brain / Q000201:enzymology* / Q000473:pathology*; D002648:Child; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008607:Intellectual Disability / Q000150:complications / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008831:Microcephaly / Q000150:complications / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D020125:Mutation, Missense / Q000235:genetics; D010375:Pedigree; D013577:Syndrome
chemical_list: D001217:Aspartate-Ammonia Ligase