Genetic Study Of Candidate Gene Region15q13-q22.3for Tourette Syndrome

Objective:Detection of the HDCgene (the histidine decarboxylase gene) mutation and the mutation frequency in Chinese Han patients with Tourette syndrome.Methods:A two-step screening strategy was conducted in this study. Mutation in the coding region and flanking sequence of the HDC gene were screened by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) in100TS patients (male/female=78/22; mean age:10.7±5.7years; mean age at onset:8.0±4.7years) in first step, and the risk of the identified variants in the first step were evaluated between enlarged TS group (120cases including the first100cases) and sex, age and ethnicity matched controls (240individuals, without family history of neurological disorders) to increase statistical sensitivity.Result:1. We performed mutation detection of the HDCgene in100Chinese Han patients with TS. Three variants were found including a C>T transition (IVS1+52C>T), was located52bp downstream to exon1and didn’t affect splicing site. A novel C>A transition (c.426C>A) in exon4, was a silent mutation (Gly142Gly), and a novel G>A transition (c.1743G>A) in exon12(Thr581Thr).2. The distributions of genotypic and allelic frequencies of the three variants in TS patients were compared with those of normal contro and it reveals that no significant difference in genotypic distributions and allelic frequencies between disease group and control subjects, suggestin variants in the HDC gene may play little or no role in TS susceptibility in Chinese Han population.3. A2×2table analysis yielded combined odds ratio (OR) for TS of1.55(95%CI:0.86-2.79) at IVS1+52C>T,1.00(95%CI:0.09-11.0at c.426C<A, and0.83(95%CI:0.43-1.61) at c.1743G>A.Conclusion:1. We identified three nucleotide heterozygous variants including IVS1+52C>T, c.426C>A and c.1743G>A, of which c.426C>A and c.1743G>A are both novel variants.2. The HDC gene may play little or no role in TS susceptibility in Chinese Han population. Objective:To evaluate whether the gene expression in chromosome15q13-q22.3region is responsible for the development of Tourette syndrome, identify the peripheral blood biomarker for TS.Methods:mRNA was extracted from peripheral blood lymphocytes. Quantitative realtime PCR on a subset of7genes including the histidine decarboxylase gene(HDC), the HERC domain and RCC-1like domain1gene(HERC1), the HERC domain and RCC-1like domain1gene(HERC2), the cholinergic receptor nicotinic alpha7gene (CHRNA7), the ubiquitin protein ligase E3A gene (UBE3A), the ubiquitin specific peptidase3gene(USP3) and the amyloid precursor protein-binding protein A2gene (APBA2) were conducted in30patients with TS and30normal controls. A significant difference was shown for the APBA2gene expression of peripheral lymphocytes between TS group and controls (fold change in expression is0.19,P<0.01). Further analysis of the difference expression in peripheral blood lymphocytes for the APBA2gene was extend to a sample of84TS patients and100healthy controls.Result:1. In the first step, quantitatively analysis of the mRNA levels in the peripheral blood lymphocytes was conducted for7genes(HDC, HERC1, HERC2, CHRNA7, UBE3A, USP3and APBA2) between30TS patients (male/female=18/12; mean age:10.0±3.3years) and30normal controls (male/female=18/12; mean age:11.3±3.8years). The results suggests that only the APBA2gene have a significant differential expression between TS and control samples (P<0.01). for the other6genes, there are no significant difference between TS group and control group (P>0.05).2. Further study was performed in a extend sample of84TS patients (male/female=68/16; mean age:9.9±4.0years) and100healthy controls (male/female=80/20; mean age:10.9±5.9years). The result suggested that the APBA2gene expression level in TS group is much lower than that in control group (fold change in expression is0.21, P<0.01).Discussion:1. The APBA2gene have a significant differential expression between Chinese Han TS and control samples (fold change in expression is0.21, P<0.01). It can be considered as potential peripheral blood biomarker for TS.2. For the other6genes(HDC, HERC1, HERC2, CHRNA7, UBE3A and USP3), there is no significant difference of the expression between TS patients and normal controls in peripheral blood lymphocytes (P>0.05).