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

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.