Exome Sequencing Identifies GNB4 Mutations as a Cause of Dominant Intermediate Charcot-Marie-Tooth Disease

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• 作者：Bing-Wen Soong¹ ; ² ; ³ ; ⁴ ; ¹³ ; Yen-Hua Huang⁵ ; ⁶ ; ¹³ ; Pei-Chien Tsai³ ; Chien-Chang Huang³ ; ⁷ ; Hung-Chuan Pan⁸ ; ⁹ ; Yi-Chun Lu¹ ; Hsin-Ju Chien¹ ; Tze-Tze Liu¹⁰ ; Ming-Hong Chang² ; ¹¹ ; Kon-Ping Lin¹ ; ² ; ³ ; Pang-Hsien Tu¹² ; Lung-Sen Kao³ ; ⁷ ; ¹⁰ ; ^{lskao@ym.edu.tw} ; Yi-Chung Lee¹ ; ² ; ³ ; ^{ycli@vghtpe.gov.tw}
• 刊名：The American Journal of Human Genetics
• 出版年：2013
• 出版时间：7 March, 2013
• 年：2013
• 卷：92
• 期：3
• 页码：422-430
• 全文大小：1076 K

文摘

Charcot-Marie-Tooth disease (CMT) is a heterogeneous group of inherited neuropathies. Mutations in approximately 45 genes have been identified as being associated with CMT. Nevertheless, the genetic etiologies of at least 30 % of CMTs have yet to be elucidated. Using a genome-wide linkage study, we previously mapped a dominant intermediate CMT to chromosomal region 3q28-q29. Subsequent exome sequencing of two affected first cousins revealed heterozygous mutation c.158G>A (p.Gly53Asp) in GNB4, encoding guanine-nucleotide-binding protein subunit beta-4 (G¦Â₄), to cosegregate with the CMT phenotype in the family. Further analysis of GNB4 in an additional 88 unrelated CMT individuals uncovered another de novo mutation, c.265A>G (p.Lys89Glu), in this gene in one individual. Immunohistochemistry studies revealed that G¦Â₄ was abundant in the axons and Schwann cells of peripheral nerves and that expression of G¦Â₄ was significantly reduced in the sural nerve of the two individuals carrying the c.158G>A (p.Gly53Asp) mutation. In?vitro studies demonstrated that both the p.Gly53Asp and p.Lys89Glu altered proteins impaired bradykinin-induced G-protein-coupled-receptor (GPCR) signaling, which was facilitated by the wild-type G¦Â₄. This study identifies GNB4 mutations as a cause of CMT and highlights the importance of G¦Â₄-related GPCR signaling in peripheral-nerve function in humans.