Exome sequencing identifies GNB4 mutations as a cause of dominant intermediate Charcot-Marie-Tooth disease

Bing Wen Soong, Yen Hua Huang, Pei Chien Tsai, Chien Chang Huang, Hung Chuan Pan, Yi Chun Lu, Hsin Ju Chien, Tze Tze Liu, Ming Hong Chang, Kon Ping Lin, Pang Hsien Tu, Lung Sen Kao, Yi Chung Lee*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

41 Scopus citations


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 (Gβ4), 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 Gβ4 was abundant in the axons and Schwann cells of peripheral nerves and that expression of Gβ4 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 Gβ4. This study identifies GNB4 mutations as a cause of CMT and highlights the importance of Gβ4-related GPCR signaling in peripheral-nerve function in humans.

Original languageEnglish
Pages (from-to)422-430
Number of pages9
JournalAmerican Journal of Human Genetics
Issue number3
StatePublished - 7 Mar 2013


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