title: Analysis of catechol-O-methyltransferase gene mutation and identification of new pathogenic gene for paroxysmal kinesigenic dyskinesia.
abstract: We aimed to analyze the mutation site and frequency of catechol-O-methyltransferase (COMT) gene, to explore the relationship between COMT genotype and phenotype, and to find new pathogenic genes for paroxysmal kinesigenic dyskinesia (PKD). PKD patients who were treated from December 2011 to January 2014 were selected and subjected to genetic testing in the exon region of COMT. Two patients and one intrafamilial healthy control were subjected to exome sequencing using whole exome capture in combination with high-throughput sequencing to find candidate pathogenic gene sites. The results were verified by Sanger sequencing. A total of 11 familial PKD patients from 4 families and 9 sporadic patients without family history were included. Pathogenic c.634dupC(p.P220fsX7) mutation of COMT gene was found in 7 familial PKD patients and3 sporadic patients. Mutated COMT gene carriers suffered from PKD earlier (average age of onset: 11.61 ± 2.33 vs 16.21 ± 2.58, P = 0.001) with symmetric symptoms in most cases, while the mutation-negative group only showed unilateral symptoms (P = 0.001). The mutation-positive group also had more daily attacks (P = 0.038). Carbamazepine worked for all mutation-positive patients (10/10, 100%), but only for a part of mutation-negative patients (3/10, 30.0%). About 90000 single nucleotide polymorphisms and 2000 insertion-deletion polymorphisms were detected in each of the three samples. c.737C → T(p.T246 M) mutation of POC1B gene was a new pathogenic site for a selected family. COMT gene mutation, which was the pathogenesis of most familial PKD patients and a part of sporadic patients, predicted the response to carbamazepine. POC1B may be a novel pathogenic gene for PKD.
authors.affiliation: Department of Neurology, Second Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu Province, China.
authors.forename: Chengzhi
authors.initials: C
authors.lastname: Gu
authors.affiliation: Department of Neurology, Second Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu Province, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Neurology, Second Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu Province, China.
authors.forename: Lianhai
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Department of Neurology, Second Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu Province, China.
authors.forename: Zhenhui
authors.initials: Z
authors.lastname: Lu
authors.affiliation: Department of Neurology, Second Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu Province, China. huanghydn@yeah.net.
authors.forename: Huaiyu
authors.initials: H
authors.lastname: Huang
mesh_terms: D000293:Adolescent; D017668:Age of Onset; D000927:Anticonvulsants / Q000627:therapeutic use; D002220:Carbamazepine / Q000627:therapeutic use; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics; D002648:Child; D004421:Dystonia / Q000188:drug therapy / Q000235:genetics*; D005190:Family; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D060005:Genotyping Techniques; D006801:Humans; D054643:INDEL Mutation; D008297:Male; D020641:Polymorphism, Single Nucleotide; D016896:Treatment Outcome
chemical_list: D000927:Anticonvulsants; D018797:Cell Cycle Proteins; C000592372:POC1B protein, human; D002220:Carbamazepine; C588010:COMT protein, human; D002394:Catechol O-Methyltransferase
keywords: Catechol-O-methyltransferase; Exome sequencing; POC1B; Paroxysmal kinesigenic dyskinesia