AGC1 deficiency associated with global cerebral hypomyelination.
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.
Wibom
Rolf
R
Center for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden.
Lasorsa
Francesco M
FM
Töhönen
Virpi
V
Barbaro
Michela
M
Sterky
Fredrik H
FH
Kucinski
Thomas
T
Naess
Karin
K
Jonsson
Monica
M
Pierri
Ciro L
CL
Palmieri
Ferdinando
F
Wedell
Anna
A
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
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