Disease relevance of SLC25A12

• Mitochondrial aspartate glutamate carrier (citrin) deficiency as the cause of adult-onset type II citrullinemia (CTLN2) and idiopathic neonatal hepatitis (NICCD) [1].
• We prepared a recombinant adenovirus encoding for human Aralar1 (AdCA-Aralar1), tagged with the small FLAG epitope [2].
• Deficiency of citrin, a liver-type mitochondrial aspartate-glutamate carrier (AGC), encoded by the SLC25A13 gene on chromosome 7q21.3, causes autosomal recessive disorders: adult-onset type II citrullinemia (CTLN2) and neonatal hepatitis associated with intrahepatic cholestasis (NICCD) [3].

Psychiatry related information on SLC25A12

• RESULTS: Linkage and association were observed between autistic disorder and the two SNPs, rs2056202 and rs2292813, found in SLC25A12 [4].
• SLC25A12 expression is associated with neurite outgrowth and is upregulated in the prefrontal cortex of autistic subjects [5].
• Rabionet, et al. tested the SLC25A12 variants rs2056202 and rs2292813 for association with autism in 327 families and failed to demonstrate association with autism [6]
• Turunen, et al. replicated the association of rs2292813 with autistic disorder in a Finnish cohort [7]
• Our data do not support that the SLC25A12 gene is associated with autism in our population [Han Chinese living in Taiwan] [8]
• This study confirmed an association between SLC25A12 and RRB traits in ASDs, but the direction of the association was different from that in the initial study. [9]
• RESULTS: rs6716901 [in SLC25A12] showed significant association with AS [Asperger's Syndrome] ( P ?=?0.008) after correcting for multiple testing. We did not replicate the previously identified association between rs2056202 and AS in our sample. [10]

High impact information on SLC25A12

• The two mammalian AGCs, aralar and citrin, are members of the malate-aspartate NADH shuttle, and citrin, the liver AGC, is also a member of the urea cycle [11].
• Citrin and aralar1 are homologous proteins belonging to the mitochondrial carrier family with EF-hand Ca(2+)-binding motifs in their N-terminal domains [12].
• The malate-aspartate NADH shuttle member Aralar1 determines glucose metabolic fate, mitochondrial activity, and insulin secretion in beta cells [2].
• Aralar amino-terminal half was shown to bind calcium by 45Ca2+ overlay and calcium-dependent mobility shift assays [13].
• The subcellular localization of the protein in COS cells transfected with Aralar was exclusively mitochondrial [13].

Chemical compound and disease context of SLC25A12

• These results demonstrate that citrin and aralar1 are isoforms of the hitherto unidentified aspartate/glutamate carrier and explain why mutations in citrin cause type II citrullinemia in humans [12].

Biological context of SLC25A12

• 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 [4].
• Assignment of the calcium-binding mitochondrial carrier Aralar1 gene (SLC25A12) to human chromosome band 2q31 by in situ hybridization [14].
• Multiple genomic screens have shown evidence suggesting linkage to chromosome 2q31-q33, which includes the SLC25A12 gene [15].
• A recent study identified a highly significant association between autism and a two-single-nucleotide-polymorphism haplotype in the SLC25A12 gene, with a homozygote genotype relative risk between 2.4 and 4 [16].
• A member of this subfamily (that we have termed Aralar) was cloned from a human heart cDNA library [13].

Anatomical context of SLC25A12

• Since the function of citrin, together with that of an isoform, aralar, was found to be as a mitochondrial aspartate glutamate carrier, the various symptoms of NICCD and CTLN2 may be understood as caused by defective aspartate export from the mitochondria to the cytosol and defects in the malate aspartate shuttle [1].
• The activity of citrin and aralar1 as aspartate/glutamate exchangers was stimulated by Ca(2+) on the external side of the inner mitochondrial membrane, where the Ca(2+)-binding domains of these proteins are localized [12].
• Although it is known that aralar1 is expressed mainly in skeletal muscle, heart and brain, whereas citrin is present in liver, kidney and heart, the precise tissue distribution of the two proteins in embryonic and adult tissues is largely unknown [17].
• The strong expression of citrin in the liver was acquired postnatally, whereas the characteristic expression of aralar1 in skeletal muscle was detected at E18 and that in the heart began early in development (E11) and was preferentially localized to auricular myocardium in late embryonic stages [17].
• SLC25A12 expression is associated with neurite outgrowth [5] .

Associations of SLC25A12 with chemical compounds

• Moreover citrin and its isoform aralar were found to be aspartate glutamate carrier [18].
• We found no evidence of association of the SLC25A12 gene with lactate and lactate/pyruvate distributions or with autism in 241 nuclear families with one affected individual [19].
• The carboxyl-terminal half of Aralar (amino acids 321-678) has high similarity with the oxoglutarate, citrate, and adenine nucleotide carriers (28-29% identity), whereas the amino-terminal half (amino acids 1-320) contains three canonical EF-hands [13].

Other interactions of SLC25A12

• Pathogenesis and pathophysiology of citrin (a mitochondrial aspartate glutamate carrier) deficiency [18].
• SLC25A12 and CMYA3 gene variants are not associated with autism in the IMGSAC multiplex family sample [20].

Analytical, diagnostic and therapeutic context of SLC25A12

• We have identified a new class of substrates, citrin and aralar1, which are Ca2+-binding aspartate/glutamate carriers (AGCs) of the mitochondrial inner membrane, using cross-linking and immunoprecipitation assays in isolated mitochondria [21].
• Molecular cloning of Aralar, a new member of the mitochondrial carrier superfamily that binds calcium and is present in human muscle and brain [13].

References