The Molecular Mechanism Of Sex Differences In The Phenotype Of Dopa-responsive Dystonia

[Objective]To analyze the pathogenic gene mutation,genotype and clinical phenotype of a family with Dopa-responsive dystonia,also to explore the molecular mechanisms of gender differences in phenotype.[Methods]This study was based on a Chinese family with a clinical diagnosis of DRD was collected.Using the Whole Exome Sequencing（WES）to screen the gene mutation in the probands.After PCR amplification,using the Sanger sequencing to detect the pathogenic gene mutation in other family members.Lymphoblastoid cell lines（LCL）of the family members were established.The cells were treated with estrogen.Using fluorescence quantitative PCR was used to detect mRNA expression level.[Results]（1）An unreported mutation site（NM₀00161:c.G331T:p.E111X）was detected,the families include five female patients,two asymptomatic males GCH1 carriers of disease-causing mutations,and three non-infected family members.（2）After administration 100 uM of 17β-E2to cells,compared with female in the normal control group,the mRNA expression of GCH1 genes is increasing,was not statistically significant.（p>0.05）;male mutation carriers compared with normal controls.There was no difference in the mRNA expression of GCH1 gene,was not statistically significant（p>0.05）;female patients compared to male mutant carriers,the mRNA expression of GCH1 genes is increasing,was not statistically significant（p>0.05）;Excluding the gender factor,patients compared with the normal controls,the mRNA expression of GCH1 genes is increasing,was not statistically significant（p>0.05）;mutation carriers compared with normal controls,there was no difference in the mRNA expression of GCH1 gene,was not statistically significant（p>0.05）.[Conclusion]The results show that the WES is an effective strategy to screen the dopa responsive dystonia which is highly heterogeneous and rare genetic diseases.This study successfully established an LCL cell model with the pathogenic mutation;Our study found that there was no significant effect on the RNA level of GCH1 in LCL cells whether or not estrogen stimulation has,there may be other factors that affect expression.