title: TGM6 identified as a novel causative gene of spinocerebellar ataxias using exome sequencing.
abstract: Autosomal-dominant spinocerebellar ataxias constitute a large, heterogeneous group of progressive neurodegenerative diseases with multiple types. To date, classical genetic studies have revealed 31 distinct genetic forms of spinocerebellar ataxias and identified 19 causative genes. Traditional positional cloning strategies, however, have limitations for finding causative genes of rare Mendelian disorders. Here, we used a combined strategy of exome sequencing and linkage analysis to identify a novel spinocerebellar ataxia causative gene, TGM6. We sequenced the whole exome of four patients in a Chinese four-generation spinocerebellar ataxia family and identified a missense mutation, c.1550T-G transition (L517W), in exon 10 of TGM6. This change is at a highly conserved position, is predicted to have a functional impact, and completely cosegregated with the phenotype. The exome results were validated using linkage analysis. The mutation we identified using exome sequencing was located in the same region (20p13-12.2) as that identified by linkage analysis, which cross-validated TGM6 as the causative spinocerebellar ataxia gene in this family. We also showed that the causative gene could be mapped by a combined method of linkage analysis and sequencing of one sample from the family. We further confirmed our finding by identifying another missense mutation c.980A-G transition (D327G) in exon seven of TGM6 in an additional spinocerebellar ataxia family, which also cosegregated with the phenotype. Both mutations were absent in 500 normal unaffected individuals of matched geographical ancestry. The finding of TGM6 as a novel causative gene of spinocerebellar ataxia illustrates whole-exome sequencing of affected individuals from one family as an effective and cost efficient method for mapping genes of rare Mendelian disorders and the use of linkage analysis and exome sequencing for further improving efficiency.
authors.affiliation: Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan Province 410008, China.
authors.forename: Jun Ling
authors.initials: JL
authors.lastname: Wang
authors.forename: Xu
authors.initials: X
authors.lastname: Yang
authors.forename: Kun
authors.initials: K
authors.lastname: Xia
authors.forename: Zheng Mao
authors.initials: ZM
authors.lastname: Hu
authors.forename: Ling
authors.initials: L
authors.lastname: Weng
authors.forename: Xin
authors.initials: X
authors.lastname: Jin
authors.forename: Hong
authors.initials: H
authors.lastname: Jiang
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.forename: Lu
authors.initials: L
authors.lastname: Shen
authors.forename: Ji Feng
authors.initials: JF
authors.lastname: Guo
authors.forename: Nan
authors.initials: N
authors.lastname: Li
authors.forename: Ying Rui
authors.initials: YR
authors.lastname: Li
authors.forename: Li Fang
authors.initials: LF
authors.lastname: Lei
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.forename: Juan
authors.initials: J
authors.lastname: Du
authors.forename: Ya Fang
authors.initials: YF
authors.lastname: Zhou
authors.forename: Qian
authors.initials: Q
authors.lastname: Pan
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Rui Qiang
authors.initials: RQ
authors.lastname: Li
authors.forename: Bei Sha
authors.initials: BS
authors.lastname: Tang
mesh_terms: D000328:Adult; D017668:Age of Onset; D044466:Asian People / Q000235:genetics; D002681:China; D002890:Chromosomes, Human, Pair 20 / Q000235:genetics; D015331:Cohort Studies; D004247:DNA / Q000235:genetics*; D030541:Databases, Genetic; D005091:Exons / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D008040:Genetic Linkage; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D016254:Mutagenesis, Insertional; D009154:Mutation / Q000235:genetics / Q000502:physiology; D020125:Mutation, Missense; D010375:Pedigree; D017354:Point Mutation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020754:Spinocerebellar Ataxias / Q000235:genetics*; D011503:Transglutaminases / Q000235:genetics*
chemical_list: D004247:DNA; C532876:TGM6 protein, human; D011503:Transglutaminases