Association of INPP1, PIK3CG, and TSC2 gene variants with autistic disorder: implications for phosphatidylinositol signalling in autism.

E pidemiological studies have shown that about 43–86% of individuals with tuberous sclerosis complex have a pervasive developmental disorder similar to autism. Mutations in tuberous sclerosis genes TSC1 and TSC2 disrupt the phosphatidylinositol signalling pathway downstream of the insulin / insulin-like growth factor receptor in the control of cell growth. We investigated single nucleotide polymorphisms in three phosphatidylinositol signalling genes that map to consensus areas of linkage to autism, using 196 trios from the Autism Genetics Resource Exchange. Polymorphisms in inositol polyphosphate-1-phosphatase (INPP1) at the 2q32, c catalytic subunit of phosphatidyl 3OH-kinase gene (PIK3CG) at 7q22, and TSC2 gene at 16p13.3, were investigated for association with autistic disorder. Transmission disequilibrium tests and haplotype analyses demonstrated a nominally positive association of polymorphisms in INPP1, PIK3CG, and TSC2 genes with autism, suggesting that phosphatidylinositol signalling may have a role in susceptibility to autism. Autism spectrum disorders [MIM 209850], which include autism, Asperger’s syndrome, and pervasive developmental disorder not otherwise specified, are characterised by impairments in communications and social interactions and the presence of stereotyped behaviours. Family, twin, and linkage data suggest that inheritance of autism is complex. Latent class analysis of twin and family data suggests that between two to 10 loci may act epistatically, although more than 15 loci have been suggested. Recent genome screening studies found that many regions distributed over many chromosomes had a multipoint maximum lod score greater than one. Several studies found evidence of linkage in overlapping regions, which are likely to represent true linkage findings. The most consistent results are for regions on chromosome 7q, 2q and 16p13.3. 15–17 The 16p13.3 region harbours the locus for TSC2 gene. Autism occurs in a number of genetic conditions, such as fragile X, 20 phenylketonuria, tuberous sclerosis complex, Rett syndrome, and chromosomal anomalies, but the majority of cases of autism are of unknown aetiology. The risk of autism in patients with tuberous sclerosis complex (TSC) is higher than in any other known condition. Epidemiological studies have shown that about 50–60% of individuals with TSC have mental retardation and 43–86% a pervasive developmental disorder similar to autism. Similarly, epidemiological studies of children with autism have reported that TSC occurs on average in 1% of cases. The possible mechanisms mediating association between tuberous sclerosis and autism include linkage disequilibrium of closely linked loci and disruption of a common neural or developmental pathway. The protein products of the TSC genes, hamartin and tuberin, appear to act as tumour suppressors. Genetic analyses in mice and Drosophila indicate that TSC1 and TSC2 function in the phosphatidylinositol signalling pathway downstream of the insulin / insulin-like growth factor receptor in the control of cell growth. 24 25 The modulation of the activity of inositol signalling molecules is carried out by several kinases and phosphatases. Examples of such modulators include the phosphatidylinositol-3-OH kinases (PI3K), PTEN (phosphatases with tensin domain), and inositol polyphosphate 1-phosphatase (INPP1). A review of the human genome maps reveals that PIK3CG, the gamma catalytic subunit of PI3K, maps to 7q22 in a consensus area of linkage to autism. 28 Similarly, the inositol polyphosphate-1-phosphatase (INPP1) gene, which codes for one of the enzymes involved in phosphatidylinositol signalling pathways, maps to 2q32, another consensus area of linkage to autism. 15–17 29 The PIK3CG, INPP1, and TSC2 genes are relatively small genes spanning 43, 30, and 41 kb of genomic DNA, respectively, with 12, 6, and 41 exons, respectively (National Center for Biotechnology Information Locus ID: 5294, 3268 and 7249). In this study, we investigated single nucleotide polymorphisms in the TSC2, INPP1, and PIK3CG genes for association with autism.