Identification of CHIP as a novel causative gene for autosomal recessive cerebellar ataxia

Yu Ting Shi, Jun Ling Wang, Jia Da Li, Hai Gang Ren, Wen Juan Guan, Miao He, Wei Qian Yan, Ying Zhou, Zheng Mao Hu, Jian Guo Zhang, Jing Jing Xiao, Zheng Su, Mei Zhi Dai, Jun Wang, Hong Jiang, Ji Feng Guo, Ya Fang Zhou, Fu Feng Zhang, Nan Li, Juan DuQian Xu, Ya Cen Hu, Qian Pan, Lu Shen, Guang Hui Wang, Kun Xia, Zhuohua Zhang, Bei Sha Tang

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    75 Citations (Scopus)


    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.

    Original languageEnglish
    Article numbere81884
    Number of pages9
    JournalPLoS One
    Issue number12
    Publication statusPublished - 2 Dec 2013


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