title: Identification of a novel Cys146X mutation of SOD1 in familial amyotrophic lateral sclerosis by whole-exome sequencing.
abstract: OBJECTIVE
  Familial amyotrophic lateral sclerosis has been linked to mutations in 15 genes, and it is believed these genes account for less than 20-30% of Chinese patients with familial amyotrophic lateral sclerosis. Of the 163 different superoxide dismutase 1 gene mutations in amyotrophic lateral sclerosis 1, only 6.1% of them were from individuals of Chinese origin. Therefore, to quickly learn the causative gene for patients with familial amyotrophic lateral sclerosis in a Chinese pedigree, we opted to apply whole-exome sequencing as a diagnostic tool.
  
  
  METHODS
  To avoid time-consuming screening of known familial amyotrophic lateral sclerosis candidate genes by PCR-Sanger sequencing, we conducted whole-exome sequencing toward selected individuals of a four-generation familial amyotrophic lateral sclerosis family.
  
  
  RESULTS
  Patients in the family showed autosomal dominant features, as well as a mean onset age of 35.3 years, and a mean duration of 2.1 years. By deep sequencing analysis, we identified a novel p.Cys146X SOD1 mutation in all examined patients. Genotype-phenotype and SOD1 structural model analysis revealed the effects of the Cys57-Cys146 disulfide bond formation and the C-terminal dimer contact region on the disease phenotypes.
  
  
  CONCLUSIONS
  The Cys146X mutation causes familial amyotrophic lateral sclerosis with severe phenotypes. Whole-exome sequencing becomes an attractive diagnostic tool for identifying causative genes, particularly for neurological disorders with unusual phenotypes, pleiotropic malformations, multiple known candidate genes, and complicated inheritance patterns.
authors.affiliation: The Institute of Genomic Medicine, Wenzhou Medical College, Wenzhou, China.
authors.forename: Jinyu
authors.initials: J
authors.lastname: Wu
authors.forename: Enjian
authors.initials: E
authors.lastname: Shen
authors.forename: Dashuang
authors.initials: D
authors.lastname: Shi
authors.forename: ZhongSheng
authors.initials: Z
authors.lastname: Sun
authors.forename: Tao
authors.initials: T
authors.lastname: Cai
mesh_terms: D000328:Adult; D000690:Amyotrophic Lateral Sclerosis / Q000175:diagnosis* / Q000208:ethnology / Q000235:genetics*; D044466:Asian People; D001483:Base Sequence; D059472:Exome; D005260:Female; D005799:Genes, Dominant; D056726:Genetic Association Studies; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010375:Pedigree; D010641:Phenotype; D017422:Sequence Analysis, DNA; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1
chemical_list: C000606290:SOD1 protein, human; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1