Genetic and expression analyses reveal elevated expression of syntaxin 1A (STX1A) in high functioning autism

Autism is a pervasive developmental disorder diagnosed in early childhood. Abnormalities of serotonergic neurotransmission have been reported in autism. Serotonin transporter (5-HTT), which modulates serotonin levels, is a major therapeutic target in autism. Therefore, factors that regulate 5-HTT expression might be implicated in autism. One candidate 5-HTT-regulatory protein is the presynaptic protein, syntaxin 1A (STX1A). We examined the association of STX1A with autism in a trio association study using DNA samples from 249 AGRE trios with autistic probands. Only male probands were selec- ted, since autism is more prevalent among males. The probands of 102 trios had IQ>70, and were con- sidered as high functioning autism (HFA). In transmission disequilibrium test (TDT) analysis, rs2293485 (p=0.034) and rs4717806 (p=0.033) showed nominal associations with HFA ; modest haplotype associ- ation was also observed. The SNPs that showed associations were related to early developmental abnor- malities (ADI-R_D). We further compared STX1A mRNA expression in the lymphocytes of drug-naive HFA patients (n=12) and age- and sex-matched controls (n=13). STX1A expression in the HFA group was significantly higher (p=0.001) than that of controls. Thus, we suggest a possible role of STX1A in the pathogenesis of HFA. During early childhood, there is a period of high brain serotonin synthesis that is disrupted in autistic children ; STX1A might influence the serotonergic system during this stage of neuro- development, as implied by the association with ADI-R_D. Received 27 September 2007 ; Reviewed 20 November 2007 ; Revised 9 May 2008 ; Accepted 14 May 2008