title: AGC1 deficiency associated with global cerebral hypomyelination.
abstract: The mitochondrial aspartate-glutamate carrier isoform 1 (AGC1), specific to neurons and muscle, supplies aspartate to the cytosol and, as a component of the malate-aspartate shuttle, enables mitochondrial oxidation of cytosolic NADH, thought to be important in providing energy for neurons in the central nervous system. We describe AGC1 deficiency, a novel syndrome characterized by arrested psychomotor development, hypotonia, and seizures in a child with a homozygous missense mutation in the solute carrier family 25, member 12, gene SLC25A12, which encodes the AGC1 protein. Functional analysis of the mutant AGC1 protein showed abolished activity. The child had global hypomyelination in the cerebral hemispheres, suggesting that impaired efflux of aspartate from neuronal mitochondria prevents normal myelin formation.
authors.affiliation: Center for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Rolf
authors.initials: R
authors.lastname: Wibom
authors.forename: Francesco M
authors.initials: FM
authors.lastname: Lasorsa
authors.forename: Virpi
authors.initials: V
authors.lastname: Töhönen
authors.forename: Michela
authors.initials: M
authors.lastname: Barbaro
authors.forename: Fredrik H
authors.initials: FH
authors.lastname: Sterky
authors.forename: Thomas
authors.initials: T
authors.lastname: Kucinski
authors.forename: Karin
authors.initials: K
authors.lastname: Naess
authors.forename: Monica
authors.initials: M
authors.lastname: Jonsson
authors.forename: Ciro L
authors.initials: CL
authors.lastname: Pierri
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Palmieri
authors.forename: Anna
authors.initials: A
authors.lastname: Wedell
mesh_terms: D026922:Amino Acid Transport Systems, Acidic / Q000172:deficiency*; D017920:Antiporters / Q000172:deficiency*; D001224:Aspartic Acid / Q000378:metabolism; D054022:Cerebrum / Q000473:pathology*; D002675:Child, Preschool; D004827:Epilepsy / Q000235:genetics*; D005260:Female; D020279:Hereditary Central Nervous System Demyelinating Diseases / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008279:Magnetic Resonance Imaging; D008928:Mitochondria / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics*; D009123:Muscle Hypotonia / Q000235:genetics; D020125:Mutation, Missense; D020033:Protein Isoforms; D011596:Psychomotor Disorders / Q000235:genetics*; D017422:Sequence Analysis, DNA; D013577:Syndrome
chemical_list: D026922:Amino Acid Transport Systems, Acidic; D017920:Antiporters; D033681:Mitochondrial Membrane Transport Proteins; D020033:Protein Isoforms; C114606:SLC25A12 protein, human; C051046:aspartate-glutamate carrier; D001224:Aspartic Acid