title: Identification of CHIP as a novel causative gene for autosomal recessive cerebellar ataxia.
abstract: Autosomal recessive cerebellar ataxias are a group of neurodegenerative disorders that are characterized by complex clinical and genetic heterogeneity. Although more than 20 disease-causing genes have been identified, many patients are still currently without a molecular diagnosis. In a two-generation autosomal recessive cerebellar ataxia family, we mapped a linkage to a minimal candidate region on chromosome 16p13.3 flanked by single-nucleotide polymorphism markers rs11248850 and rs1218762. By combining the defined linkage region with the whole-exome sequencing results, we identified a homozygous mutation (c.493CT) in CHIP (NM_005861) in this family. Using Sanger sequencing, we also identified two compound heterozygous mutations (c.389AT/c.441GT; c.621C>G/c.707GC) in CHIP gene in two additional kindreds. These mutations co-segregated exactly with the disease in these families and were not observed in 500 control subjects with matched ancestry. CHIP colocalized with NR2A, a subunit of the N-methyl-D-aspartate receptor, in the cerebellum, pons, medulla oblongata, hippocampus and cerebral cortex. Wild-type, but not disease-associated mutant CHIPs promoted the degradation of NR2A, which may underlie the pathogenesis of ataxia. In conclusion, using a combination of whole-exome sequencing and linkage analysis, we identified CHIP, encoding a U-box containing ubiquitin E3 ligase, as a novel causative gene for autosomal recessive cerebellar ataxia.
authors: Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.
authors: Yuting
authors: Y
authors: Shi
authors: Junling
authors: J
authors: Wang
authors: Jia-Da
authors: JD
authors: Li
authors: Haigang
authors: H
authors: Ren
authors: Wenjuan
authors: W
authors: Guan
authors: Miao
authors: M
authors: He
authors: Weiqian
authors: W
authors: Yan
authors: Ying
authors: Y
authors: Zhou
authors: Zhengmao
authors: Z
authors: Hu
authors: Jianguo
authors: J
authors: Zhang
authors: Jingjing
authors: J
authors: Xiao
authors: Zheng
authors: Z
authors: Su
authors: Meizhi
authors: M
authors: Dai
authors: Jun
authors: J
authors: Wang
authors: Hong
authors: H
authors: Jiang
authors: Jifeng
authors: J
authors: Guo
authors: Yafang
authors: Y
authors: Zhou
authors: Fufeng
authors: F
authors: Zhang
authors: Nan
authors: N
authors: Li
authors: Juan
authors: J
authors: Du
authors: Qian
authors: Q
authors: Xu
authors: Yacen
authors: Y
authors: Hu
authors: Qian
authors: Q
authors: Pan
authors: Lu
authors: L
authors: Shen
authors: Guanghui
authors: G
authors: Wang
authors: Kun
authors: K
authors: Xia
authors: Zhuohua
authors: Z
authors: Zhang
authors: Beisha
authors: B
authors: Tang
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000378:metabolism; D002524:Cerebellar Ataxia / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005260:Female; D008040:Genetic Linkage; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D021381:Protein Transport; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: C467728:STUB1 protein, human; D044767:Ubiquitin-Protein Ligases