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Am J Hum Genet. 2014 Nov 6;95(5):590-601. doi: 10.1016/j.ajhg.2014.10.002. Epub 2014 Oct 30.

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

Author information

1
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.
2
Neuromuscular Unit, Mossakowski Medical Research Centre Polish Academy of Sciences, Centre of Biostructure, Medical University of Warsaw, Pawinskiego 5, 02-106 Warsaw, Poland.
3
VIB Department of Molecular Genetics, University of Antwerp, Antwerpen 2610, Belgium.
4
Institute of Genetic Medicine, MRC Centre for Neuromuscular Diseases, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
5
Division of Neuropathology and Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
6
Clinic of Central and Peripheral Degenerative Neuropathies Unit, IRCCS Foundation, C. Besta Neurological Institute, Via Celoria 11, 20133 Milan, Italy.
7
Clinic for Neurology and Psychiatry for Children and Youth, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia.
8
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.
9
Department of Medical Genetics, Centre of Biostructure, Medical University of Warsaw, Pawinskiego 5, 02-106 Warsaw, Poland.
10
University of Belgrade, Faculty of Medicine, 11000 Belgrade, Serbia.
11
MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
12
Neurogenetics Laboratory, The National Hospital for Neurology and Neurosurgery and UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
13
Unit of Genetics of Neurodegenerative and Metabolic Disease IRCCS Foundation, C. Besta Neurological Institute, Via Celoria 11, 20133 Milan, Italy.
14
Child Neurology Unit, IRCCS Foundation, C. Besta Neurological Institute, Via Celoria 11, 20133 Milan, Italy.
15
John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, FL 33136, USA.
16
Department of Molecular Neurosciences, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
17
Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
18
Christian-Albrechts-University, 24118 Kiel, Germany.
19
SPZ Pediatric Neurology, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany.
20
Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, Singapore 138673.
21
Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, Singapore 138673; Life Sciences Institute, Zhejiang University, Hangzhou 310058, People's Republic of China.
22
Department of Neurology, Sungkyunkwan University School of Medicine, Seoul 137-710, Korea.
23
Department of Biological Science, Kongju National University, Chungnam 134-701, Korea.
24
Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
25
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.

Abstract

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.

PMID:
25439726
PMCID:
PMC4225647
DOI:
10.1016/j.ajhg.2014.10.002
[Indexed for MEDLINE]
Free PMC Article

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