| BackgroundsDystonia, including torsion dystonia, blepharospasm, oromandibular dystonia, cervical dystonia, dysphonia and writer’s cramp, is a group of related movement disorders characterized by abnormal repetitive, twisting postures due to the involuntary co-contraction of opposing muscle groups. Sometimes tremor can be the only clinical presentation. The pathogenesis of dystonia is not completely understood. Until now, over20genes have been identified to be associated with primary dystonia among which DYT25/GNAL is newly discovered in2012. The research of GNAL is on its preliminary stage and screening of mutations in GNAL in large number of Chinese patients with primary dystonia is insufficient.ObjectivesWe aim to determine the mutation rate and hot spot mutation of GNAL in a large cohort of214Chinese patients with primary dystonia, including12familial cases.MethodsWe recruited214Chinese patients with primary dystonia who were admitted to the Movement Disorders and Botulinum Toxin-A treatment center in Peking Union Medical College Hospital. Control DNA samples were obtained from100Chinese unrelated healthy individuals. Genomic DNA was prepared from peripheral venous blood of each subject. Polymerase chain reactions (PCR) was used to amplify DNA fragments of12exons and5’UTR region of GNAL and mutational screening was performed by direct sequencing. Any mutations identified in the patients were screened in the controls by PCR amplification and sequencing. Influence on the mutated proteins was analyzed by bioinformatics software. Also, mutation rates of GNAL in different populations were calculated by reviewing all published studies screening for mutations of GNAL.ResultsWe identified11variants in the12exons and5’UTR region of GNAL:c.-37A>G, c.-41T>C, c.-111C>T, c.-116A>G, c.-142G>C, c.-485T>C, c.15C>T (p.G5=), c.30G>T (p.T10=), c.44G>A (p.G15D), c.1059C>T (p.A353=) and c.360C>T (p.S120=). Among these, c.360C>T(p.S120=), c.-111C>T, c.-41T>C, c.-37A>G, c.30G>T(p.T10=) and c.44G>A (p.G15D) were proved to be SNPs (rs76888098, rs61495657, rs9303742, rs200432196, rs78167172and rs199761315) and were not pathogenic mutations. c.15C>T (p.G5=), c.30G>T (p.T10=), c.1059C>T (p.A353=) and c.360C>T (p.S120=) were synonymous mutations and protein were not changed. Mutation Taster revealed that c.-485T>C, c.-142G>C, c.-116A>G were polymorphism and not pathogenic as well. These variants were not detected in healthy controls. By reviewing the previous studies, we found mutation rates of GNAL varied greatly in different populations, ranging from0%to15.38%.ConclusionsIn summary, we did not identify any mutations in GNAL that could be a cause of the dystonia in214cases drawn from China, including12familial cases. Our own data suggest that GNAL mutations do not represent a common cause of primary dystonia, as least in Chinese population. BackgroundsCervical dystonia (CD), the most common form of primary focal dystonia, is characterized by involuntary muscle contractions of the cervical musculature, leading to twisting or abnormal postures. The cause of cervical dystonia is unknown; however, there is evidence for a genetic component to its etiology. Mutations in CIZ1, ANO3and GNAL have recently been associated with primary dystonia, especially craniocervical dystonia. Until now, there is no genetic study of patients with familial cervical dystonia in China.ObjectivesWe aim to determine the mutation rates of CIZ1, ANO3and GNAL in twenty cervical dystonia pedigrees of Chinese Han population.MethodsWe recruited20cervical dystonia pedigrees of Chinese Han population who were admitted to the Movement Disorders and Botulinum Toxin-A treatment center in Peking Union Medical College Hospital. Control DNA samples were obtained from100Chinese unrelated healthy individuals. Genomic DNA was prepared from peripheral venous blood of each subject. Polymerase chain reactions (PCR) was used to amplify DNA fragments of all exons of CIZ1, ANO3and GNAL and5’UTR region of GNAL of20probands. Mutational screening was performed by direct sequencing. Any mutations identified in the probands were screened in the controls by PCR amplification and sequencing. Influence on the mutated proteins was analyzed by bioinformatics software. Also, mutation rates of CIZ1, ANO3and GNAL were calculated in our study.ResultsWe identified two synonymous mutations in the CIZ1gene:c.696G>A (p.P232=) and c.1227C>A (p.P409=), which proved to be SNPs rs45579839and rs455590357. Also,7variants were detected in the ANO3gene:c.-11G>T, c.1158A>G (p.L386=), c.1692A>C (p.A564=), c.2682C>T (p.P894=), c.2478C>G,(p.T826=), c.2520T>G (p.R840=) and c.2540A>G(p.Y847C). Among these, c.1158A>G(p.L386=), c.1692A>C(p.A564=) and c.2682C>T (p.P894=) were also found in the control group. c.-11G>T, c.1158A>G (p.L386=), c.1692A>C (p.A564=) and c.2682C>T (p.P894=) were proved to be SNPs: rs143269109, rs2663168, rs11604768and rs10835051. c.2478C>G (p.T826=) and c.2520T>G (p.R840=) were synonymous mutations leading no change in amino acids. In addition, a missense mutation, c.2540A>G (p.Y847C) was found in Family S with cervical dystonia and dystonic tremor. This variant was predicted to be damaging by all3programs and not found in previous studies. Clustal Omega analysis of the protein in different species showed mutation conservation. No variants were found in the GNAL gene.ConclusionsIn summary, we identified one missense mutation in AN03, c.2540A>G (p.Y847C) in20cervical dystonia pedigrees in China. No pathogenic mutations were found in CIZ1and GNAL gene. The mutation rate of ANO3gene in familial cervical dystonia patients is5%(1/20). Our study also suggests that mutations in CIZ1and GNAL are not a common cause of familial cervical dystonia, as least in Chinese Han population. BackgroundsDystonia, including torsion dystonia, blepharospasm, oromandibular dystonia, cervical dystonia, dysphonia and writer’s cramp, is a group of related movement disorders characterized by abnormal repetitive, twisting postures due to the involuntary co-contraction of opposing muscle groups. Sometimes tremor can be the only clinical presentation. Brain-derived neurotrophic factor (BDNF) is a modulator of synaptic and neural plasticity. Considering the association between dystonia and abnormal sensorimotor cortex plasticity, BDNF may be a candidate gene that confers susceptibility to dystonia. However, the association between Va166Met polymorphism of BDNF gene and primary dystonia is controversial.ObjectivesWe aim to assess the association between the Va166Met polymorphism of BDNF gene and primary dystonia in China.MethodsA case-control study was performed to evaluate the association between Va166Met polymorphism in the BDNF gene and primary dystonia in a cohort of252Chinese patients and in214age-and gender-matched healthy control subjects. Genotyping was carried out using SNaPshot technology. Data was processed by SPSS13.0and Analysis of Variance (ANOVA) was used to compare the genotype and allele distribution between the groups.ResultsNo association was identified between Va166Met polymorphism and primary dystonia or cervical dystonia (P=0.309and P=0.803respectively).In a subsequent subgroup analysis, there was also no difference in the distribution for age of onset.ConclusionsOur findings do not support that Va166Met polymorphism of BDNF gene contributes to the risk of primary dystonia in China. |
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