title: Exome sequencing identifies GNB4 mutations as a cause of dominant intermediate Charcot-Marie-Tooth disease.
abstract: 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.
authors: Department of Neurology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors: Bing-Wen
authors: BW
authors: Soong
authors: Yen-Hua
authors: YH
authors: Huang
authors: Pei-Chien
authors: PC
authors: Tsai
authors: Chien-Chang
authors: CC
authors: Huang
authors: Hung-Chuan
authors: HC
authors: Pan
authors: Yi-Chun
authors: YC
authors: Lu
authors: Hsin-Ju
authors: HJ
authors: Chien
authors: Tze-Tze
authors: TT
authors: Liu
authors: Ming-Hong
authors: MH
authors: Chang
authors: Kon-Ping
authors: KP
authors: Lin
authors: Pang-Hsien
authors: PH
authors: Tu
authors: Lung-Sen
authors: LS
authors: Kao
authors: Yi-Chung
authors: YC
authors: Lee
mesh_terms: D000293:Adolescent; D000328:Adult; D001369:Axons / Q000378:metabolism; D001920:Bradykinin / Q000235:genetics / Q000378:metabolism; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics*; D002648:Child; D059472:Exome; D005260:Female; D044387:GTP-Binding Protein beta Subunits / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010523:Peripheral Nervous System Diseases / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA / Q000379:methods; D055815:Young Adult
chemical_list: C534984:GNB4 protein, human; D044387:GTP-Binding Protein beta Subunits; D043562:Receptors, G-Protein-Coupled; D001920:Bradykinin