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.

AGC1 Deficiency Causes Infantile Epilepsy, Abnormal Myelination, and Reduced N-Acetylaspartate

“…2d), the glutamate carrier, and also in many other mitochondrial carrier subfamilies, thereby confirming its importance in the function and/or structure of mitochondrial carriers rather than in substrate binding (Palmieri 2013). The Arg353Gln mutation occurs in a different domain of the AGC1 transporter from the Gln590Arg mutation that was previously reported in one subject (Wibom et al 2009). The Gln590Arg mutation involves an amino acid residue that protrudes into the internal cavity of the AGC1 carrier immediately above the substrate binding site (Wibom et al 2009).…”

“…The Arg353Gln mutation occurs in a different domain of the AGC1 transporter from the Gln590Arg mutation that was previously reported in one subject (Wibom et al 2009). The Gln590Arg mutation involves an amino acid residue that protrudes into the internal cavity of the AGC1 carrier immediately above the substrate binding site (Wibom et al 2009). In contrast, the Arg353Gln mutation involves an amino acid residue that is located just below the m-gate of the carrier and is thought to participate in closing and opening the carrier on the matrix side through an interaction with a highly conserved glutamate at residue 384 ( Fig.…”

“…The myelination defect primarily stems from neuronal loss attributable to the energy deficit caused by a lack of cellular reducing equivalents generated by the glutamate-aspartate shuttle (Wolf and van der Knaap 2009). The brain insult is possibly compounded by a lack of neuronal-generated NAA that is required as a precursor by oligodendrocytes to synthesize myelin and would lead to the secondary hypomyelination also observed in these patients (Wibom et al 2009). As reduced NAA can be indicative of either decreased NAA production or neuronal loss, it is not possible to discern which mechanism predominates in AGC1 deficiency.…”

“…Indeed, this is only the second report of autosomal recessive SLC25A12 mutations causing severe neurologic disease. The initial 2009 report linking SLC25A12 to neurologic disease involved a Swedish girl who was found by candidate gene sequencing to harbor a homozygous AGC1 mutation that caused infantile-onset severe psychomotor retardation, hypotonia, epilepsy, global cerebral hypomyelination, and dramatically decreased NAA (Wibom et al 2009). SLC25A12 encodes a neuronal-specific mitochondrial aspartate-glutamate carrier (aspartate-glutamate carrier isoform 1, AGC1).…”

“…A distinct disorder, AGC2 deficiency, results from SLC25A13 mutations that reduce aspartate-glutamate carrier isoform 2 (AGC2) function with impaired malate/aspartate shuttle activity in the liver (Saheki and Kobayashi 2002). The prior report in the Swedish infant demonstrated complete loss of recombinant mutant AGC1 activity, resulting in no transport of aspartate or glutamate even after a 60 min incubation period (Wibom et al 2009). In contrast, the homozygous c.1058G>A missense mutation identified in this consanguineous Indian family reduces recombinant mutant AGC1 activity to approximately 15 % of the initial wild-type rate, as determined when measuring either aspartate transport or glutamate transport.…”