2. Academic Validation
  3. Identification of CHIP as a novel causative gene for autosomal recessive cerebellar ataxia

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

  • PLoS One. 2013 Dec 2;8(12):e81884. doi: 10.1371/journal.pone.0081884.
Yuting Shi 1,  Junling Wang,  Jia-Da Li,  Haigang Ren,  Wenjuan Guan,  Miao He,  Weiqian Yan,  Ying Zhou,  Zhengmao Hu,  Jianguo Zhang,  Jingjing Xiao,  Zheng Su,  Meizhi Dai,  Jun Wang,  Hong Jiang,  Jifeng Guo,  Yafang Zhou,  Fufeng Zhang,  Nan Li,  Juan Du,  Qian Xu,  Yacen Hu,  Qian Pan,  Lu Shen,  Guanghui Wang,  Kun Xia,  Zhuohua Zhang,  Beisha Tang
Affiliations

Affiliation

  • 1 Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.
PMID: 24312598 DOI: 10.1371/journal.pone.0081884
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.

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