A novel mutation in VCP causes Charcot-Marie-Tooth Type 2 disease

  • Brain. 2014 Nov;137(Pt 11):2897-902. doi: 10.1093/brain/awu224.
Michael A Gonzalez  1 ,  Shawna M Feely  2 ,  Fiorella Speziani  1 ,  Alleene V Strickland  1 ,  Matt Danzi  1 ,  Chelsea Bacon  2 ,  Youjin Lee  3 ,  Tsui-Fen Chou  4 ,  Susan H Blanton  1 ,  Conrad C Weihl  3 ,  Stephan Zuchner  5 ,  Michael E Shy  6
Affiliations
  • 1. 1 Dr John T Macdonald Department of Human Genetics and John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
  • 2. 2 Department of Neurology, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242, USA.
  • 3. 3 Department of Neurology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA.
  • 4. 4 Division of Medical Genetics, Department of Paediatrics, Harbor-UCLA Medical Centre and Los Angeles Biomedical Research Institute, Torrance, CA 90502, USA.
  • 5. 1 Dr John T Macdonald Department of Human Genetics and John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA [email protected] [email protected].
  • 6. 2 Department of Neurology, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242, USA [email protected] [email protected].
PMID: 25125609 DOI: 10.1093/brain/awu224
Abstract

Mutations in VCP have been reported to account for a spectrum of phenotypes that include inclusion body myopathy with Paget's disease of the bone and frontotemporal dementia, hereditary spastic paraplegia, and 1-2% of familial Amyotrophic Lateral Sclerosis. We identified a novel VCP mutation (p.Glu185Lys) segregating in an autosomal dominant Charcot-Marie-Tooth disease type 2 family. Functional studies showed that the Glu185Lys variant impaired autophagic function leading to the accumulation of immature autophagosomes. VCP mutations should thus be considered for genetically undefined Charcot-Marie-Tooth disease type 2.

Keywords
autophagy; hereditary motor and sensory neuropathies; neurodegeneration; neuropathy; whole-exome sequencing.