Truncating and missense mutations in IGHMBP2 cause Charcot-Marie Tooth disease type 2

Ellen Cottenie; Andrzej Kochanski; Albena Jordanova; Boglarka Bansagi; Magdalena Zimon; Alejandro Horga; Zane Jaunmuktane; Paola Saveri; Vedrana Milic Rasic; Jonathan Baets; Marina Bartsakoulia; Rafal Ploski; Pawel Teterycz; Milos Nikolic; Ros Quinlivan; Matilde Laura; Mary G Sweeney; Franco Taroni; Michael P Lunn; Isabella Moroni; Michael Gonzalez; Michael G Hanna; Conceicao Bettencourt; Elodie Chabrol; Andre Franke; Katja von Au; Markus Schilhabel; Dagmara Kabzińska; Irena Hausmanowa-Petrusewicz; Sebastian Brandner; Siew Choo Lim; Haiwei Song; Byung-Ok Choi; Rita Horvath; Ki-Wha Chung; Stephan Zuchner; Davide Pareyson; Matthew Harms; Mary M Reilly; Henry Houlden

doi:10.1016/j.ajhg.2014.10.002

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Truncating and missense mutations in IGHMBP2 cause Charcot-Marie Tooth disease type 2

Journal article

Open access

Peer reviewed

Truncating and missense mutations in IGHMBP2 cause Charcot-Marie Tooth disease type 2

Ellen Cottenie, Andrzej Kochanski, Albena Jordanova, Boglarka Bansagi, Magdalena Zimon, Alejandro Horga, Zane Jaunmuktane, Paola Saveri, Vedrana Milic Rasic, Jonathan Baets, …

American journal of human genetics, Vol.95(5), pp.590-601

2014-11-06

DOI: https://doi.org/10.1016/j.ajhg.2014.10.002

PMCID: PMC4225647

PMID: 25439726

Abstract

Humans

Models, Molecular

Molecular Sequence Data

Chromosome Mapping

Charcot-Marie-Tooth Disease - pathology

Sequence Analysis, DNA

Mutation, Missense - genetics

Charcot-Marie-Tooth Disease - genetics

Protein Interaction Mapping

Haplotypes - genetics

Exome - genetics

Phenotype

Sural Nerve - pathology

Pedigree

Base Sequence

Adult

Female

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-μ-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.

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.255 Musculoskeletal Disorders; 1.255.2204 Spinal Muscular Atrophy
Web Of Science research areas: Genetics & Heredity
ESI research areas: Molecular Biology & Genetics

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Title: Truncating and missense mutations in IGHMBP2 cause Charcot-Marie Tooth disease type 2
Creators: Ellen Cottenie - MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK; Department of Molecular Neurosciences, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK
Andrzej Kochanski - Neuromuscular Unit, Mossakowski Medical Research Centre Polish Academy of Sciences, Centre of Biostructure, Medical University of Warsaw, Pawinskiego 5, 02-106 Warsaw, Poland
Albena Jordanova - VIB Department of Molecular Genetics, University of Antwerp, Antwerpen 2610, Belgium
Boglarka Bansagi - Institute of Genetic Medicine, MRC Centre for Neuromuscular Diseases, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK
Magdalena Zimon - VIB Department of Molecular Genetics, University of Antwerp, Antwerpen 2610, Belgium
Alejandro Horga - MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK; Department of Molecular Neurosciences, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK
Zane Jaunmuktane - Division of Neuropathology and Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK
Paola Saveri - Clinic of Central and Peripheral Degenerative Neuropathies Unit, IRCCS Foundation, C. Besta Neurological Institute, Via Celoria 11, 20133 Milan, Italy
Vedrana Milic Rasic - Clinic for Neurology and Psychiatry for Children and Youth, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
Jonathan Baets - VIB Department of Molecular Genetics, University of Antwerp, Antwerpen 2610, Belgium; Laboratory of Neurogenetics, University of Antwerp, Antwerpen 2610, Belgium; Department of Neurology, Antwerp University Hospital, Antwerpen, Belgium
Marina Bartsakoulia - Institute of Genetic Medicine, MRC Centre for Neuromuscular Diseases, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK
Rafal Ploski - Department of Medical Genetics, Centre of Biostructure, Medical University of Warsaw, Pawinskiego 5, 02-106 Warsaw, Poland
Pawel Teterycz - Department of Medical Genetics, Centre of Biostructure, Medical University of Warsaw, Pawinskiego 5, 02-106 Warsaw, Poland
Milos Nikolic - University of Belgrade, Faculty of Medicine, 11000 Belgrade, Serbia
Ros Quinlivan - MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK
Matilde Laura - MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK; Department of Molecular Neurosciences, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK
Mary G Sweeney - Neurogenetics Laboratory, The National Hospital for Neurology and Neurosurgery and UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK
Franco Taroni - Unit of Genetics of Neurodegenerative and Metabolic Disease IRCCS Foundation, C. Besta Neurological Institute, Via Celoria 11, 20133 Milan, Italy
Michael P Lunn - MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK
Isabella Moroni - Child Neurology Unit, IRCCS Foundation, C. Besta Neurological Institute, Via Celoria 11, 20133 Milan, Italy
Michael Gonzalez - John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, FL 33136, USA
Michael G Hanna - MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK; Department of Molecular Neurosciences, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK
Conceicao Bettencourt - Department of Molecular Neurosciences, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK
Elodie Chabrol - Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK
Andre Franke - Christian-Albrechts-University, 24118 Kiel, Germany
Katja von Au - SPZ Pediatric Neurology, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany
Markus Schilhabel - Christian-Albrechts-University, 24118 Kiel, Germany
Dagmara Kabzińska - Neuromuscular Unit, Mossakowski Medical Research Centre Polish Academy of Sciences, Centre of Biostructure, Medical University of Warsaw, Pawinskiego 5, 02-106 Warsaw, Poland
Irena Hausmanowa-Petrusewicz - Neuromuscular Unit, Mossakowski Medical Research Centre Polish Academy of Sciences, Centre of Biostructure, Medical University of Warsaw, Pawinskiego 5, 02-106 Warsaw, Poland
Sebastian Brandner - Division of Neuropathology and Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK
Siew Choo Lim - Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, Singapore 138673
Haiwei Song - Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, Singapore 138673; Life Sciences Institute, Zhejiang University, Hangzhou 310058, People's Republic of China
Byung-Ok Choi - Department of Neurology, Sungkyunkwan University School of Medicine, Seoul 137-710, Korea
Rita Horvath - Institute of Genetic Medicine, MRC Centre for Neuromuscular Diseases, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK
Ki-Wha Chung - Department of Biological Science, Kongju National University, Chungnam 134-701, Korea
Stephan Zuchner - John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, FL 33136, USA
Davide Pareyson - Clinic of Central and Peripheral Degenerative Neuropathies Unit, IRCCS Foundation, C. Besta Neurological Institute, Via Celoria 11, 20133 Milan, Italy
Matthew Harms - Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA
Mary M Reilly - MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK; Department of Molecular Neurosciences, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK
Henry Houlden - MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK; Department of Molecular Neurosciences, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK; Neurogenetics Laboratory, The National Hospital for Neurology and Neurosurgery and UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK. Electronic address: h.houlden@ucl.ac.uk
Publication Details: American journal of human genetics, Vol.95(5), pp.590-601
Publisher: United States
Grant note: G108/638 / Medical Research Council MR/J004758/1 / Medical Research Council Wellcome Trust G1001253 / Medical Research Council G0802760 / Medical Research Council 309548 / European Research Council R01 NS075764 / NINDS NIH HHS G0601943 / Medical Research Council U54NS065712 / NINDS NIH HHS R01NS075764 / NINDS NIH HHS MR/K000608/1 / Medical Research Council 096919 / Wellcome Trust U54 NS065712 / NINDS NIH HHS
Academic Unit: Leadership Department; Miller School of Medicine; John P. Hussman Institute for Human Genomics
Language: English
Resource Type: Journal article
PMID: 25439726
PMCID: PMC4225647
Record Identifier: 991031577648902976