Resequencing and Association Analysis of <i>PTPRA</i>, a Possible Susceptibility Gene for Schizophrenia and Autism Spectrum Disorders

<div><p>Background</p><p>The <i>PTPRA</i> gene, which encodes the protein RPTP-α, is critical to neurodevelopment. Previous linkage studies, genome-wide association studies, controlled expression analyses and animal models support an association with both schizophrenia and autism spectrum disorders, both of which share a substantial portion of genetic risks.</p><p>Methods</p><p>We sequenced the protein-encoding areas of the <i>PTPRA</i> gene for single nucleotide polymorphisms or small insertions/deletions (InDel) in 382 schizophrenia patients. To validate their association with the disorders, rare (minor allele frequency <1%), missense mutations as well as one InDel in the 3′UTR region were then genotyped in another independent sample set comprising 944 schizophrenia patients, 336 autism spectrum disorders patients, and 912 healthy controls.</p><p>Results</p><p>Eight rare mutations, including 3 novel variants, were identified during the mutation-screening phase. In the following association analysis, L59P, one of the two missense mutations, was only observed among patients of schizophrenia. Additionally, a novel duplication in the 3′UTR region, 174620_174623dupTGAT, was predicted to be located within a Musashi Binding Element.</p><p>Major Conclusions</p><p>No evidence was seen for the association of rare, missense mutations in the <i>PTPRA</i> gene with schizophrenia or autism spectrum disorders; however, we did find some rare variants with possibly damaging effects that may increase the susceptibility of carriers to the disorders.</p></div

In silico functional effect prediction for rs61742029 and L59P.

<p>In silico functional effect prediction for rs61742029 and L59P.</p

Evolutionary conservation information for rs61742029 and L59P

<p>*Marks the position of the amino acid change due to mutation.</p><p>Evolutionary conservation information for rs61742029 and L59P</p

Targeted sequencing areas of the <i>PTPRA</i> Gene.

<p>Targeted sequencing areas of the <i>PTPRA</i> Gene.</p

Structure of the <i>PTPRA</i> gene, RPTP-α, and position of discovered rare missense mutations.

<p>Structure of the <i>PTPRA</i> gene, RPTP-α, and position of discovered rare missense mutations.</p

Profiles of participants in the resequencing and association sample sets.

<p>Note: Some samples in the association study group were not identified by sex.</p><p>Profiles of participants in the resequencing and association sample sets.</p

Association analysis results of two rare missense mutations and one 3'UTR variant.

<p>Notes:</p>a<p>: Homozygote of minor allele/heterozygote/homozygote of major allele.</p>b<p>: Calculated using Fisher′s exact test, one-tailed.</p><p>Ctrl: healthy controls.</p><p>Association analysis results of two rare missense mutations and one 3'UTR variant.</p

Rare exonic mutations identified during the resequencing stage.

<p>Notes:</p>a<p>: Based on NCBI build 37.1.</p>b<p>: Based on NCBI Reference Sequence NC_000020.10.</p>c<p>: Based on NCBI Reference Sequence NP_001099043. AA: amino acid.</p><p>All mutations are heterozygous.</p><p>Rare exonic mutations identified during the resequencing stage.</p