Clinical and Neuroimaging Features in Charcot-Marie-Tooth Patients with GNB4 Mutations.

Hye Mi Kwon,Jae Hong Park,Ki Wha Chung,Soo Hyun Nam,Sang Beom Kim,Da Eun Nam,Ah Jin Lee,Byung-Ok Choi,Hyun Su Kim,Soohyun Hwang

doi:10.3390/life11060494

Abstract

Charcot–Marie–Tooth disease (CMT) is the most common inherited peripheral neuropathy. Mutations in the GNB4 gene cause dominant intermediate CMT type F (CMTDIF). The aim of this study is to investigate phenotypic heterogeneities and characteristics of CMT patients with GNB4 mutations. We enrolled 1143 Korean CMT families and excluded 344 families with a PMP22 duplication. We further analyzed the 799 remaining families to find their GNB4 mutations using whole-exome sequencing (WES). We identified two mutations (p.Gly77Arg and p.Lys89Glu) in three families, among which a heterozygous p.Gly77Arg mutation was novel. In addition, a significant uncertain variant (p.Thr177Asn) was observed in one family. The frequency of the GNB4 mutation in the Korean population is 0.38% in PMP22 duplication-negative families. All three families showed de novo mutation. Electrophysiological findings regarding the p.Lys89Glu mutation showed that the motor nerve conduction velocity (MNCV) of the median nerve was markedly reduced, indicating demyelinating neuropathy, and sural nerve biopsy revealed severe loss of myelinated axons with onion bulb formation. Lower extremity Magnetic Resonance Imaging (MRI) demonstrated relatively more severe intramuscular fat infiltrations in demyelinating type (p.Lys89Glu mutation) patients compared to intermediate type (p.Gly77Arg mutation) patients. The anterolateral and superficial posterior compartment muscles of the distal calf were preferentially affected in demyelinating type patients. Therefore, it seems that the investigated GNB4 mutations do cause not only the known intermediate type but also demyelinating-type neuropathy. We first presented three Korean families with GNB4 mutations and found phenotypic heterogeneities of both intermediate and demyelinating neuropathy. We suggest that those findings are useful for the differential diagnosis of CMT patients with unknown GNB4 variants.

Highlights

Charcot–Marie–Tooth disease (CMT) is a genetically and clinically heterogeneous disorder characterized by distal muscle weakness, sensory loss, and areflexia [1,2]
We identified two pathogenic variants and an uncertain significant variant from GNB4 in four CMT families (Supplementary Table S1)
We described the first known Korean families with GNB4 mutations, including a novel p.Gly77Arg mutation

Summary

Introduction

Charcot–Marie–Tooth disease (CMT) is a genetically and clinically heterogeneous disorder characterized by distal muscle weakness, sensory loss, and areflexia [1,2]. The GNB4 gene (MIM 610863) encodes guanine-nucleotide-binding protein subunit beta-4 (Gb4), which is widely expressed in many tissues including axons and Schwann cells of peripheral nerves [8,9]. Mutant GNB4 proteins cause problems in the G proteincoupled receptor (GPCR) signaling pathway including dysfunction of nerve cells and axons, peripheral neuropathy, and scoliosis [10,11,12]. Soon et al suggested a dominant-negative effect of GNB4 mutant proteins in the GPCR signaling of peripheral nerves as a pathogenic mechanisms [13]. Mutations in the GNB4 gene cause dominant intermediate CMT type F (CMTDIF, MIM 615185) [13]. Based on the nerve conduction study, patients with p.Gly53Asp or p.Gln220Arg mutations showed CMTDIF

Objectives

Methods

Results

Conclusion