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Genetic, transcriptional and biochemical studies of the mitochondrial aspartate/glutamate…
in this region (8-10) . Among nine candidate genes recently screened for association
with autism across the 2q31 region, the SLC25A12 gene encoding a mitochondrial
aspartate/glutamate transporter (ARALAR) was the only locus displaying
a significant association with two single nucleotide polymorphisms (SNPs)
located in the third and sixteenth introns, i.e. rs2056202 (I3–21A/G) and
rs2292813 (I16+70A/G), respectively (2) . This genetic association has already
been replicated in another independent sample (3) .
The mitochondrial aspartate/glutamate carrier (ARALAR) catalyzes an
important step in the aspartate/malate NADH shuttle, namely the exchange of
aspartate and glutamate across the inner mitochondrial membrane (11) .
Through this activity, ARALAR regulates the redox state and energy balance
across mitochondrial membranes inside the cells. Importantly, ARALAR carries
EF-hand Ca 2+ -binding motifs in its N terminal domain, and transport rates
are significantly enhanced by calcium concentrations in the external side of the
mitochondrial membrane (11) . Very recent preliminary data indicate that
ARALAR overexpression may result in enhanced neurite growth in vitro (12) .
This finding, in conjunction with the positive genetic association described
above, spurs interest into the potential involvement of ARALAR overexpression
and/or overactivation in autism.
Altered neurodevelopment is indeed currently recognized as the underlying
neuropathological cause of autistic disorder. The central nervous system (CNS)
of individuals with autism processes information by activating neural networks
clearly distinct from those employed by non-autistic individuals (13,14) .
The neuroanatomical substrates of this altered information processing appear
as heterogeneous as clinical manifestations and etiological underpinnings.
Post-mortem studies of autistic brains have uncovered a variety of neurodevelopmental
alterations, encompassing many aspects of CNS formation, such as
reduced programmed cell death and/or increased cell proliferation, altered cell
migration with disrupted cortical and subcortical cytoarchitectonics, abnormal
cell differentiation with reduced neuronal size, unbalanced local vs long-distance
and inhibitory vs excitatory connectivity, and altered synaptogenesis (15) .
However, excessive neurite outgrowth and reduced terminal pruning during
infancy is believed to play a critical role in the establishment of megalencephaly
(i.e., fronto-occipital head circumference > 97 th percentile), an anomaly consistently
found in approximately 20% of autistic patients (16,17) . Brain imaging studies
have shown an enlargement of total brain volume and of temporal, parietal
and occipital lobes in male patients with autism (18) , as well as early postnatal
brain overgrowth followed by abnormally slow brain growth (19) .
Our group has already demonstrated genetic contributions to cranial circumference
in autistic children by HoxA1 gene variants (20) . Thanks to the availability
of temporal cortical tissue specimens from the Autism Tissue Program
(Princeton, NJ, USA) and of a very large sample of families where cranial circumference
has been assessed in the autistic proband, our group is in a unique
position to test the hypothesis that genetic variants at the SLC25A12 gene,
yielding an hyperactive ARALAR, and/or overactivation due to increased intracellular
calcium concentrations, may cause autism in a specific subset of
patients characterized by megalencephaly.
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