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

Ellen Cottenie,Jonathan Baets,Haiwei Song,Zane Jaunmuktane,Paola Saveri,Sebastian Brandner,Davide Pareyson,Isabella Moroni,Albena Jordanova,Rita Horvath,Dagmara Kabzińska,Marina Bartsakoulia,Henry Houlden,Michael Gonzalez,Franco Taroni,Alejandro Horga,Markus B Schilhabel ,Katja Von Au ,Andrzej Kochański ,Matthew Harms ,I Hausmanowa-Pétrusewicz ,Michael P Lunn ,Mary M Reilly ,Rafał Płoski ,Byung Ok Choi ,Conceição Bettencourt ,Stephan Züchner ,Ki Wha Chung ,V Milić Rašić ,R Quinlivan ,Mary G Sweeney ,Miloš Nikolić ,Boglárka Bánsági ,André Franke ,Siew Choo Lim ,M Zimoń ,Paweł Teterycz ,Matilde Laurá ,E Chabrol ,Michael G Hanna

doi:10.1016/j.ajhg.2014.10.002

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.

Highlights

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)
We initially studied a family where two siblings were affected with CMT2
Known mutations in genes implicated in CMT2 were excluded by Sanger sequencing and whole-exome sequencing and linkage analysis were carried out, with informed consent and IRB ethics approval UCL/University College London Hospitals (UCLH)

Summary

REPOR T

Truncating and Missense Mutations in IGHMBP2 Cause Charcot-Marie Tooth Disease Type 2. Chest Xray and sleep study was normal; nerve conduction studies and sural nerve biopsy indicated an axonal neuropathy (Figure 2) Her sister had milder clinical features, and examination findings at the age of 40 years revealed bilateral foot drop, distal weakness, and wasting in the upper and lower limbs and areflexia. The cDNA analysis identified that the stop mutation was hemizygous, suggesting a deletion on the other allele (Figure S3; Table 1)

Protein Change

AFOþCrutches No

Abs Abs

Findings

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