Linkage and association of the mitochondrial aspartate/ glutamate carrier SLC25A12 gene with autism
ABSTRACT Autism/autistic disorder (MIM number 209850) is a complex, largely genetic psychiatric disorder. The authors recently mapped a susceptibility locus for autism to chromosome region 2q24-q33 (MIM number 606053). In the present study, genes across the 2q24-q33 interval were analyzed to identify an autism susceptibility gene in this region.
Mutation screening of positional candidate genes was performed in two stages. The first stage involved identifying, in unrelated subjects showing linkage to 2q24-q33, genetic variants in exons and flanking sequence within candidate genes and comparing the frequency of the variants between autistic and unrelated nonautistic subjects. Two single nucleotide polymorphisms (SNPs) that showed evidence for divergent distribution between autistic and nonautistic subjects were identified, both within SLC25A12, a gene encoding the mitochondrial aspartate/glutamate carrier (AGC1). In the second stage, the two SNPs in SLC25A12 were further genotyped in 411 autistic families, and linkage and association tests were carried out in the 197 informative families.
Linkage and association were observed between autistic disorder and the two SNPs, rs2056202 and rs2292813, found in SLC25A12. Using either a single affected subject per family or all affected subjects, evidence for excess transmission was found by the Transmission Disequilibrium Test for rs2056202, rs2292813, and a two-locus G*G haplotype. Similar results were observed using TRANSMIT for the analyses. Evidence for linkage was supported by linkage analysis with the two SNPs, with a maximal multipoint nonparametric linkage score of 1.57 and a maximal multipoint heterogeneity lod score of 2.11. Genotype relative risk could be estimated to be between 2.4 and 4.8 for persons homozygous at these loci.
A strong association of autism with SNPs within the SLC25A12 gene was demonstrated. Further studies are needed to confirm this association and to decipher any potential etiological role of AGC1 in autism.
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ABSTRACT: The aspartate/glutamate carrier isoform 1 is an essential mitochondrial transporter that exchanges intramitochondrial aspartate and cytosolic glutamate across the inner mitochondrial membrane. It is expressed in brain, heart and muscle and is involved in important biological processes, including myelination. However, the signals that regulate the expression of this transporter are still largely unknown. In this study we first identify a CREB binding site within the aspartate/glutamate carrier gene promoter that acts as a strong enhancer element in neuronal SH-SY5Y cells. This element is regulated by active, phosphorylated CREB protein and by signal pathways that modify the activity of CREB itself and, most noticeably, by intracellular Ca2+ levels. Specifically, aspartate/glutamate carrier gene expression is induced via CREB by forskolin while it is inhibited by the PKA inhibitor, H89. Furthermore, the CREB-induced activation of gene expression is increased by thapsigargin, which enhances cytosolic Ca2+, while it is inhibited by BAPTA-AM that reduces cytosolic Ca2+ or by STO-609, which inhibits CaMK-IV phosphorylation. We further show that CREB-dependent regulation of aspartate/glutamate carrier gene expression occurs in neuronal cells in response to pathological (inflammation) and physiological (differentiation) conditions. Since this carrier is necessary for neuronal functions and is involved in myelinogenesis, our results highlight that targeting of CREB activity and Ca2+ might be therapeutically exploited to increase aspartate/glutamate carrier gene expression in neurodegenerative diseases.The international journal of biochemistry & cell biology 01/2015; 60. DOI:10.1016/j.biocel.2015.01.004 · 4.24 Impact Factor
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ABSTRACT: Autism spectrum disorders (ASDs) encompass a range of syndromes that are characterised by social interaction impairments, verbal and nonverbal communication difficulties, and stereotypic or repetitive behaviours. Although there has been considerable progress in understanding the mechanisms underlying the changes in the 'social' and 'communicative' aspects of ASD, the neurofunctional architecture of repetitive and stereotypic behaviours, as well as other cognitive domains related to response and action control, remain poorly understood. Based on the findings of neurobiological and neuroanatomical alterations in ASD and the functional neuroanatomy and neurobiology of different action control functions, we emphasise that changes in action control processes, including response inhibition, conflict and response monitoring, task switching, dual-tasking, motor timing, and error monitoring, are important facets of ASD. These processes must be examined further to understand the executive control deficits in ASD that are related to stereotypic or repetitive behaviours as a major facet of ASD. The review shows that not all domains of action control are strongly affected in ASD. Several factors seem to determine the consistency with which alterations in cognitive control are reported. These factors relate to the relevance of neurobiological changes in ASD for the cognitive domains examined and in how far action control relies upon the adjustment of prior experience. Future directions and hypotheses are outlined that may guide basic and clinical research on action control in ASD.Progress in Neurobiology 11/2014; DOI:10.1016/j.pneurobio.2014.11.002 · 10.30 Impact Factor
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ABSTRACT: Increasing evidence suggests that autism is associated with abnormal white-matter (WM) anatomy and impaired brain 'connectivity'. While myelin plays a critical role in synchronized brain communication, its aetiological role in autistic symptoms has only been indirectly addressed by WM volumetric, relaxometry and diffusion tensor imaging studies. A potentially more specific measure of myelin content, termed myelin water fraction (MWF), could provide improved sensitivity to myelin alteration in autism.Psychological Medicine 08/2014; 45(04):1-11. DOI:10.1017/S0033291714001858 · 5.43 Impact Factor