Clinical and genetic features of Charcot-Marie-Tooth disease patients with IGHMBP2 mutations

Liu Lei; Lin Zhiqiang; Li Xiaobo; Hu Zhengmao; Huang Shunxiang; Zhao Huadong; Tang Beisha; Zhang Ruxu

doi:10.1016/j.nmd.2022.05.002

Clinical and genetic features of Charcot-Marie-Tooth disease patients with IGHMBP2 mutations

Neuromuscul Disord. 2022 Jul;32(7):564-571. doi: 10.1016/j.nmd.2022.05.002. Epub 2022 May 11.

Authors

Liu Lei¹, Lin Zhiqiang², Li Xiaobo², Hu Zhengmao³, Huang Shunxiang², Zhao Huadong², Tang Beisha⁴, Zhang Ruxu⁵

Affiliations

¹ Health Management Center, the Third Xiangya Hospital, Central South University, Changsha, China; Department of Neurology, the Third Xiangya Hospital, Central South University, Changsha, China.
² Department of Neurology, the Third Xiangya Hospital, Central South University, Changsha, China.
³ Provincial Key Laboratory of Medical Genetics, Central South University, Changsha, China.
⁴ Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.
⁵ Department of Neurology, the Third Xiangya Hospital, Central South University, Changsha, China. Electronic address: zhangruxu@vip.163.com.

PMID: 35660062
DOI: 10.1016/j.nmd.2022.05.002

Abstract

Autosomal recessive Charcot-Marie-Tooth disease Type 2S (AR-CMT2S) caused by IGHMBP2 mutation was first reported in 2014, and an increasing number of cases have been reported in the past eight years. We detected 15 distinct IGHMBP2 mutations among 8 typical AR-CMT2S families in our cohort of 178 Chinese CMT2 families using Sanger sequencing and next-generation sequencing (NGS), making IGHMBP2 mutations the most frequent cause of AR-CMT2 in our cohort. From 2014 to 2022, 34 AR-CMT2S families, including 45 patients and 47 different mutations, were reported. One third of identified mutations represented presumed loss-of-function variants (nonsense, frameshift and splicing), while two-thirds were missense changes which clustered in the helicase and ATPase domains. The age at onset ranged from 0.11 years to 20 years (mean±SD: 3.76±3.93 years) and the infantile (0-2 years) onset group accounted for the most patients (51.1%). The initial symptoms included muscle weakness (15, 33.3%), delayed milestones (9, 20%), feet deformity (8, 17.8%), gait disturbance (8, 17.8%), feet drop (7, 15.6%), frequent falls (3, 6.7%), hypotonia (2, 4.4%) and thenar atrophy (1, 2.2%). Molecular structural model analysis of 26 missense IGHMBP2 mutations using PyMOL software revealed that six mutations were close to the RNA-binding channel, eight mutations were in or close to the nucleotide-binding pocket. Based on available limited clinical information, it seems possible that missense changes located in or close to these motifs might be linked to a more severe clinical outcome. In conclusion, IGHMBP2 mutation screening should recommended for early-onset, moderately or severely affected, and sporadic or AR-CMT2 patients. A tiny minority of patients were relatively late onset and mild affected, which should be given more attention in genetic diagnosis and treatment. While our preliminary analysis suggests a potential link between the localization of missense mutations and clinical presentation, definition of genotype-phenotype relationships will require harmonized clinical information from a larger series of patients.

Keywords: AR-CMT2S; Genotype; IGHMBP2; Molecular structural model analysis; Phenotype.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Charcot-Marie-Tooth Disease* / genetics
Cohort Studies
DNA-Binding Proteins* / genetics
Humans
Mutation
Mutation, Missense
Phenotype
Transcription Factors* / genetics

Substances

DNA-Binding Proteins
IGHMBP2 protein, human
Transcription Factors