Phenotypes and cellular effects of GJB1 mutations causing CMT1X in a cohort of 226 Chinese CMT families.
The aim of this study is to explore the phenotypic and genotypic features of X-linked Charcot-Marie-Tooth (CMT) disease in the mainland of China and to study the cellular effects of six novel Gap junction protein beta-1 variants. We identified 25 missense and 1 non-sense mutations of GJB1 in 31 unrelated families out of 226 CMT families. The frequency of GJB1 mutations was 13.7% of the total and 65% of intermediate CMT. Six novel GJB1 variants (c.5A>G, c.8G>A, c.242T>C, c.269T>C, c.317T>C and c.434T>G) were detected in six unrelated intermediate CMT families. Fluorescence revealed that HeLa cells transfected with EGFP-GJB1-V74M, EGFP-GJB1-L81P or EGFP-GJB1-L90P had diffuse endoplasmic reticulum staining, HeLa cells transfected with EGFP-GJB1-L106P had diffuse intracellular staining, and HeLa cells transfected with EGFP-GJB1-N2S had cytoplasmic and nuclear staining. The distribution of Cx32 in HeLa cells transfected with EGFP-GJB1-F145C was similar to that of those transfected with wild-type (WT). These six variants resulted in a higher percentage of apoptosis than did WT as detected by flow cytometry and Hoechst staining. In conclusion, mutation screening should be first performed in intermediate CMT patients, especially those with additional features. The novel GJB1 variants c.5A>G, c.8G>A, c.242T>C and c.269T>C are considered pathogenic, and c.317T>C and c.434T>G are classified as probably pathogenic.
Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, China.
L
L
Liu
Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, China.
X B
XB
Li
National Key Lab of Medical Genetics, Central South University, Changsha, China.
Z H M
ZHM
Hu
Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, China.
X H
XH
Zi
Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, China.
X
X
Zhao
Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, China.
Y Z
YZ
Xie
Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, China.
S H X
SHX
Huang
National Key Lab of Medical Genetics, Central South University, Changsha, China.
K
K
Xia
National Key Lab of Medical Genetics, Central South University, Changsha, China.|Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.
B S
BS
Tang
Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, China.
R X
RX
Zhang
D000293:Adolescent; D000328:Adult; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000503:physiopathology; D002648:Child; D002681:China; D015331:Cohort Studies; D017630:Connexins / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006367:HeLa Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D000097002:Gap Junction beta-1 Protein
D017630:Connexins; D000097002:Gap Junction beta-1 Protein
CMT1X; GJB1 mutations; apoptosis; cellular expression