PMC:3852299 / 19882-24001 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/3852299","sourcedb":"PMC","sourceid":"3852299","source_url":"http://www.ncbi.nlm.nih.gov/pmc/3852299","text":"Genetics of SERT in ASD\nASD is a genetically inherited disorder and SERT has been the focus of much research due to its prominent role in serotonin homeostasis. SERT is encoded by the SLC6A4 (Solute carrier family 6 (neurotransmitter transporter, serotonin, member 4) gene. Several gene variants of SLC6A4 that are associated with ASD alter the structure, function or expression of SERT [47]. SERT functions in all serotonergic systems through transport-mediated regulation of serotonin release and activation of homo- and hetero-receptors in brain, platelets and peripheral organs. Changes in the function of SERT alters the affinity and expression of serotonin receptors, as well as the pharmacokinetics of serotonin [47]. Human SLC6A4 maps onto chromosome 17q11.2 [95] and it is one of several genetic loci that has been identified as predisposing to ASD [96,97]. The gene is composed of 15 exons spanning approximately 40 kb. The sequence of the transcript predicts a protein containing 630 amino acids with 12 transmembrane domains. Alternative promoters and splicing of the code involving exons 1A, B, C and the 3’ untranslated region results in variable mRNA products. Polymorphisms, which alter the expression of the SLC6A4 gene and therefore, SERT protein levels, have been the focus of research into the genetic inheritance of ASD and as such, polymorphisms within the 5-HTTLPR promoter sequence, mutations in the coding sequence, or intronic mutations of the SERT have been reported to be linked to ASD in some but not all studies [1,47,89]. Two major polymorphisms in the SERT gene have been of major interest. First, a variable number of tandem repeats (VNTR) occurs in the second intron of the gene [98]. Second, basal and induced human SERT gene transcription is differentially modulated by allelic variants of the SERT gene promoter [98]. The SLC6A4 5-HTTLPR promoter sequence is located approximately 1 kb upstream of the transcription initiation site, contains two variable repeat length polymorphisms known as long (L) with 16 repeat elements, or the 44-base pair (bp) shorter (S) variant with 14 repeat elements [95,99], which determines the expression of the SERT in the pre-synaptic axonic membranes. The L/L variant of the 5-HTTLPR promoter region expresses significantly (1.4- to 2.0-fold) more transporter protein compared to L/S or S/S variants [100,101]. Higher SERT mRNA levels and increased serotonin uptake is evident in lymphoblasts of the L/L homozygotes compared to those with at least one copy of the S allele [102]. The S/S polymorphism reduces transcriptional efficiency of the SERT promoter to reduce the SERT expression and serotonin uptake in lymphoblasts [102]. Therefore the L/L variant was proposed to contribute to a lower concentration in the synaptic cleft, although this is not consistently supported by the literature [100]. The S/S polymorphism has been reported to be associated with psychiatric disorders including neuroticism [99] schizophrenia [103], anxiety [104], depression [105], suicide [106,107], ASD [108] and GI syndromes such as irritable bowel syndrome [109,110].\nThe L variant is also correlated with higher rates of serotonin uptake into platelets [111,112], suggesting that the S variant may act as a dominant allele [101]. The results of multiple studies of the 5-HTTLPR and ASD have been inconsistent, showing an association of the short [113-116] or long allele [117,118], and some studies have found no association [119-121].\nThere is substantial evidence that ASD is genetically inherited and current research has evaluated many polymorphisms that could alter SERT expression in ASD without consistent results, suggesting that the genetic changes associated with SERT have yet to be identified. At the same time ASD is associated with multiple polymorphisms in the SLC6A4 gene with individuals heterozygous for the Gly56Ala plus 5-HTTLPR L/L promoter variants [73], and other studies into SLC6A4 and other psychiatric disorders suggests that haplotypes (multiple alleles) that include the 5-HTTLPR variants may contribute to this disorder 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