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Identification and functional characterization of novel GDAP1 variants in Chinese patients with Charcot-Marie-Tooth disease
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  • Zhi-Ying Wu,
  • Cong-Xin Chen,
  • Jia-Qi Li,
  • Hai-Lin Dong,
  • Ge Bai
Zhi-Ying Wu
Second Affiliated Hospital,Zhejiang University School of Medicine
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Cong-Xin Chen
First Affiliated Hospital of Fujian Medical University
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Jia-Qi Li
1. Zhejiang University School of Medicine Second Affiliated Hospital, Department of Neurology Hangzhou, Zhejiang, CN
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Hai-Lin Dong
1. Zhejiang University School of Medicine Second Affiliated Hospital, Department of Neurology Hangzhou, Zhejiang, CN
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Ge Bai
NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University
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Abstract

Variants in the ganglioside-induced differentiation associated protein 1 (GDAP1) gene is responsible for a demyelinating form of Charcot- Marie-Tooth disease (CMT4A), an axonal form of CMT2K and an intermediate form of CMTRIA. In this study, multiplex ligation-dependent probe amplification (MLPA) and whole-exome sequencing (WES) were performed in 30 unrelated CMT patients. We identified 10 pathogenic variants in 3 known CMT related genes, including 3 novel variants (p.L26R, p.S169fs, c.694+1G>A) and one known pathogenic variant (p.R120W) in GDAP1. Functional studies were performed and the pathogenicity of novel GDAP1 variants were classified. The effect of c.694+1G>A on pre-mRNA was verified via minigene splice assay. Cellular biological effects showed an ultrastructure damage of mitochondrial, reduced protein levels, different patterns of mitochondrial dynamics, decreased mitochondrial membrane potential (Δψm), ATP content, and defects in respiratory capacity in the patient carrying p.L26R and p.S169fs in GDAP1. Further we described the clinical features of patients carrying pathogenic variants in GDAP1 and found that almost all Chinese CMT patients with GDAP1 variants present axonal type. Our results broaden the genetic spectrum of GDAP1 and provided functional evidence for mitochondrial pathways in the pathogenesis of GDAP1 variants.