Toggle Main Menu Toggle Search

Open Access padlockePrints

Truncating and Missense Mutations in IGHMBP2 Cause Charcot-Marie Tooth Disease Type 2

Lookup NU author(s): Dr Boglarka Bansagi, Marina Bartsakoulia, Professor Michael Hanna, Professor Rita HorvathORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Using a combination of exome sequencing and linkage analysis, we investigated an English family with two affected siblings in their 40s with recessive Charcot-Marie Tooth disease type 2 (CMT2). Compound heterozygous mutations in the immunoglobulin-helicase-mu-binding protein 2 (IGHMBP2) gene were identified. Further sequencing revealed a total of 11 CMT2 families with recessively inherited IGHMBP2 gene mutations. IGHMBP2 mutations usually lead to spinal muscular atrophy with respiratory distress type 1 (SMARD1), where most infants die before 1 year of age. The individuals with CMT2 described here, have slowly progressive weakness, wasting and sensory loss, with an axonal neuropathy typical of CMT2, but no significant respiratory compromise. Segregating IGHMBP2 mutations in CMT2 were mainly loss-of-function nonsense in the 5' region of the gene in combination with a truncating frameshift, missense, or homozygous frameshift mutations in the last exon. Mutations in CMT2 were predicted to be less aggressive as compared to those in SMARD1, and fibroblast and lymphoblast studies indicate that the IGHMBP2 protein levels are significantly higher in CMT2 than SMARD1, but lower than controls, suggesting that the clinical phenotype differences are related to the IGHMBP2 protein levels.

Publication metadata

Author(s): Cottenie E, Kochanski A, Jordanova A, Bansagi B, Zimon M, Horga A, Jaunmuktane Z, Saveri P, Rasic VM, Baets J, Bartsakoulia M, Ploski R, Teterycz P, Nikolic M, Quinlivan R, Laura M, Sweeney MG, Taroni F, Lunn MP, Moroni I, Gonzalez M, Hanna MG, Bettencourt C, Chabrol E, Franke A, von Au K, Schilhabel M, Kabzinska D, Hausmanowa-Petrusewicz I, Brandner S, Lim SC, Song HW, Choi BO, Horvath R, Chung KW, Zuchner S, Pareyson D, Harms M, Reilly MM, Houlden H

Publication type: Article

Publication status: Published

Journal: American Journal of Human Genetics

Year: 2014

Volume: 95

Issue: 5

Pages: 590-601

Print publication date: 06/11/2014

Online publication date: 30/10/2014

Acceptance date: 01/10/2014

Date deposited: 07/08/2015

ISSN (print): 0002-9297

ISSN (electronic): 1537-6605

Publisher: Cell Press


DOI: 10.1016/j.ajhg.2014.10.002


Altmetrics provided by Altmetric


Funder referenceFunder name
Association Belge contre les Maladies Neuromusculaires (ABMM)
French Muscular Dystrophy Association (AFM)
Medical Research Council (MRC UK)
Muscular Dystrophy Campaign (MDC)
National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre (BRC)
Randerson Foundation
Brain Research Trust (BRT)
CMT Association
Muscular Dystrophy Association (MDA)
Wellcome Trust
17 3016Ministry of Science and Technological Development, Republic of Serbia
17 508Ministry of Science and Technological Development, Republic of Serbia
309548European Research Council
G0601943MRC Neuromuscular Diseases Centre grant
FWO G054313NFund for Scientific Research-Flanders
TOP BOF 29069University of Antwerp
U54NS065712National Institutes of Neurological Diseases and Stroke and office of Rare Diseases