Clinical and mutational spectrum of Japanese patients with Charcot‐Marie‐Tooth disease caused by <i><scp>GDAP1</scp></i> variants

Yoshimura, Akinobu; Yuan, Jun‐Hui; Hashiguchi, Akihiro; Hiramatsu, Yoshihiro; Ando, Masahiro; Higuchi, Yujiro; Nakamura, Tomonori; Okamoto, Yuji; Matsumura, Kiichiro; Hamano, Toshiaki; Sawaura, Noriko; Shimatani, Yoshimitsu; Kumada, Satoko; Okumura, Yoshinori; Miyahara, Junichi; Yamaguchi, Yoshitaka; Kitamura, Shigekazu; Haginoya, Kazuhiro; Mitsui, Jun; Ishiura, Hiroyuki; Tsuji, Shoji; Takashima, Hiroshi

doi:10.1111/cge.13002

Cited by 14 publications

(17 citation statements)

References 32 publications

(67 reference statements)

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“…Previous studies in the Chinese population showed a similar frequency 4,9 . In studies conducted in other Asian CMT patients, the frequency of GDAP1 mutation ranged from 1 to 2.8%, 6,8,23 which was generally lower than those reported in the Mediterranean region (5.4%–11.5%) 24‐28 …”

Section: Discussionmentioning

confidence: 63%

“…Previous studies in the Chinese population showed a similar frequency. 4,9 In studies conducted in other Asian CMT patients, the frequency of GDAP1 mutation ranged from 1 to 2.8%, 6,8,23 which was generally lower than those reported in the Mediterranean region (5.4%-11.5%). [24][25][26][27][28] It is noticeable, however, all the patients with GDAP1 variants in our study presented the axonal type of neuropathy which was consistent with previous studies in Chinese patients except one of the patients reported by He J.…”

Section: Discussionmentioning

confidence: 82%

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Identification and functional characterization of novel GDAP1 variants in Chinese patients with Charcot–Marie–Tooth disease

Chen

Dong

et al. 2020

Ann Clin Transl Neurol

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Objective: To identify and characterize the pathogenicity of novel variants in Chinese patients with Charcot-Marie-Tooth disease. Methods: Multiplex ligation-dependent probe amplification (MLPA) and whole-exome sequencing (WES) were performed in 30 unrelated CMT patients. Minigene assay was used to verify the effect of a novel splicing variant (c.694+1G>A) on pre-mRNA. Primary fibroblast cell lines were established from skin biopsies to characterize the biological effects of the novel variants p.L26R and p.S169fs. The mitochondrial structure was observed by an electron microscope. The expression level of protein was analyzed by Western Blotting. Mitochondrial dynamics and mitochondrial membrane potential (MMP, Dwm) were analyzed via immunofluorescence study. Mitochondrial ATP levels were analyzed via bioluminescence assay. The rate of oxygen consumption was measured with a Seahorse Bioscience XF-96 extracellular flux analyzer. Results: We identified 10 pathogenic variants in three known CMT related genes, including three novel variants (p.L26R, p.S169fs, c.694+1G>A) and one known pathogenic variant (p.R120W) 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. The effect of c.694+1G>A on pre-mRNA was verified via minigene splice assay. Cellular biological effects showed ultrastructure damage of mitochondrial, reduced protein levels, different patterns of mitochondrial dynamics, decreased mitochondrial membrane potential (Dwm), ATP content, and defects in respiratory capacity in the patient carrying p.L26R and p.S169fs in GDAP1. Interpretation: Our results broaden the genetic spectrum of GDAP1 and provided functional evidence for mitochondrial pathways in the pathogenesis of GDAP1 variants.

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Section: Discussionmentioning

confidence: 63%

Section: Discussionmentioning

confidence: 82%

Identification and functional characterization of novel GDAP1 variants in Chinese patients with Charcot–Marie–Tooth disease

Chen

Dong

et al. 2020

Ann Clin Transl Neurol

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“…We have described the procedure of sequencing and data analysis previously 10 . However, this methodology could not identify some variants due to the false negative hybridization and a low‐detection efficiency of the DNA microarray in our laboratory 11 . Thus, we combined whole‐exome sequencing to overcome these issues.…”

Section: Methodsmentioning

confidence: 99%

Genetic spectrum of Charcot–Marie–Tooth disease associated with myelin protein zero gene variants in Japan

et al. 2020

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We aimed to reveal the genetic features associated with MPZ variants in Japan. From April 2007 to August 2017, 64 patients with 23 reported MPZ variants and 21 patients with 17 novel MPZ variants were investigated retrospectively. Variation in MPZ variants and the pathogenicity of novel variants was examined according to the American College of Medical Genetics standards and guidelines. Age of onset, cranial nerve involvement, serum creatine kinase (CK), and cerebrospinal fluid (CSF) protein were also analyzed. We identified 64 CMT patients with reported MPZ variants. The common variants observed in Japan were different from those observed in other countries. We identified 11 novel pathogenic variants from 13 patients. Six novel MPZ variants in eight patients were classified as likely benign or uncertain significance. Cranial nerve involvement was confirmed in 20 patients. Of 30 patients in whom serum CK levels were evaluated, eight had elevated levels. Most of the patients had age of onset >20 years. In another subset of 30 patients, 18 had elevated CSF protein levels; four of these patients had spinal diseases and two had enlarged nerve root or cauda equina. Our results suggest genetic diversity across patients with MPZ variants.

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“…Proposed roles in mitochondrial transport, redox processes, calcium homeostasis, and energy production. Baxter et al, 2002;Cuesta et al, 2002;Ammar et al, 2003;Senderek et al, 2003;Di Maria et al, 2004;Zhang et al, 2004;Baránková et al, 2007;Kabzińska et al, 2007;Auer-Grumbach et al, 2008;Rougeot et al, 2008;Xin et al, 2008;Moroni et al, 2009;Sahin-Calapoglu et al, 2009a,b;Cassereau et al, 2011;Fusco et al, 2011;Zimoń et al, 2011Zimoń et al, , 2015Vital et al, 2012;Auranen et al, 2013;Manganelli et al, 2015;Martin et al, 2015;Dohrn et al, 2017;Ho et al, 2017;Martí et al, 2017;Yoshimura et al, 2017;He et al, 2018;Masingue et al, 2018;Rzepnikowska and Kochański, 2018;Mai et al, 2019;Qin et al, 2019 De Sandre-Giovannoli et al, 2002;Chaouch et al, 2003;Hamadouche et al, 2008;Zhang et al, 2010;Liang et al, 2016;Dohrn et al, 2017 (Continued) Kijima et al, 2005;Lawson et al, 2005;Engelfried et al, 2006;Verhoeven et al, 2006;Zuchner et al, 2006;Loiseau...…”

Section: Weedon Et Al 2011 Gars1/cmt2d/601472unclassified

Impaired Mitochondrial Mobility in Charcot-Marie-Tooth Disease

Schiavon

Shadel

Manor

2021

Front. Cell Dev. Biol.

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Charcot-Marie-Tooth (CMT) disease is a progressive, peripheral neuropathy and the most commonly inherited neurological disorder. Clinical manifestations of CMT mutations are typically limited to peripheral neurons, the longest cells in the body. Currently, mutations in at least 80 different genes are associated with CMT and new mutations are regularly being discovered. A large portion of the proteins mutated in axonal CMT have documented roles in mitochondrial mobility, suggesting that organelle trafficking defects may be a common underlying disease mechanism. This review will focus on the potential role of altered mitochondrial mobility in the pathogenesis of axonal CMT, highlighting the conceptional challenges and potential experimental and therapeutic opportunities presented by this “impaired mobility” model of the disease.

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Clinical and mutational spectrum of Japanese patients with Charcot‐Marie‐Tooth disease caused by GDAP1 variants

Abstract: We identified GDAP1 variants in approximately 1% of our cohort with IPNs, and established a founder mutation in half of these patients. Our study originally described the mutational spectrum and clinical features of GDAP1-related CMT patients in Japan.

Cited by 14 publications

References 32 publications

Identification and functional characterization of novel GDAP1 variants in Chinese patients with Charcot–Marie–Tooth disease

Identification and functional characterization of novel GDAP1 variants in Chinese patients with Charcot–Marie–Tooth disease

Genetic spectrum of Charcot–Marie–Tooth disease associated with myelin protein zero gene variants in Japan

Impaired Mitochondrial Mobility in Charcot-Marie-Tooth Disease

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