| Summary: | 碩士 === 慈濟大學 === 分子生物暨人類遺傳學系碩士班 === 99 === Autism spectrum disorder (ASD) is a group of heterogeneous neurodevelopment disorders. Previous studies showed that ASD is highly heritable; nevertheless, the disease-causing genes are still unknown. Recent research suggests that genomic rearrangement may increase the burden of ASD. We recently reported a terminal deletion at the short arm of chromosome 8 in a boy with ASD. One of the genes in the deleted region is the Rho guanine nucleotide exchange factor 10 (ARHGEF10) that has been found to be associated with neuronal development in previous studies. To investigate whether the ARHGEF10 is associated with ASD in general, we set out to screen mutations of this gene in ASD. We adopted DHPLC (Denaturing High Performance Liquid Chromatography) and PCR-based direct sequencing to screen mutations at the promoter and all the exonic regions of this gene in a sample of 230 male and 26 female ASD patients and 200 control subjects. We identified several rare mutations, including D96N, G187S, E189V, I700V, T970M, T1173S, I1241F, Y1282C, and S1320R. All the mutations were confirmed by repeated sequencing and restriction fragment length polymorphism analysis (RFLP) if appropriate. Family studies showed that all the mutations were inherited from the parents. We predicted the impact of these mutations on the function of ARHGEF10 gene using computer programs PolyPhen (Polymorphism Phenotyping) and SIFT (Sorting Intolerant From Tolerant), and found that only the T1173S was predicted to be deleterious. Nevertheless, we found the total number of rare mutations of the ARHGEF10 gene was significantly over-represented in ASD as compared to control subjects, suggesting rare mutations in the ARHGEF10 gene may confer increased risk to ASD.
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