Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 95, Issue 5, Pages 590-601Publisher
CELL PRESS
DOI: 10.1016/j.ajhg.2014.10.002
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Funding
- Medical Research Council (MRC UK)
- Wellcome Trust
- Brain Research Trust (BRT)
- French Muscular Dystrophy Association (AFM)
- MRC Neuromuscular Diseases Centre grant [G0601943]
- National Institutes of Neurological Diseases and Stroke and office of Rare Diseases [U54NS065712]
- University of Antwerp [TOP BOF 29069]
- Fund for Scientific Research-Flanders [FWO G054313N]
- Ministry of Science and Technological Development, Republic of Serbia [17 3016, 17 508]
- NIH [U54NS065712, R01NS075764]
- CMT Association
- Muscular Dystrophy Campaign (MDC)
- Muscular Dystrophy Association (MDA)
- European Research Council [309548]
- Randerson Foundation
- Association Belge contre les Maladies Neuromusculaires (ABMM)
- EU [2012-305121]
- National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre (BRC)
- National Research Foundation of Korea [22A20130000039] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
- Medical Research Council [G1001253, G0601943, G0802760, MR/K000608/1, G108/638, MR/J004758/1] Funding Source: researchfish
- MRC [MR/J004758/1, G0802760, G108/638, G1001253, G0601943, MR/K000608/1] Funding Source: UKRI
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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.
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