Original Article

SIMPLE mutation in demyelinating neuropathy and distribution in sciatic nerve

  1. Craig L. Bennett PhD1,*,
  2. Andrew J. Shirk BSc1,
  3. Huy M. Huynh BSc1,
  4. Valerie A. Street PhD2,
  5. Eva Nelis PhD3,
  6. Lionel Van Maldergem MD, PhD4,
  7. Peter De Jonghe MD, PhD3,5,
  8. Albena Jordanova PhD3,5,
  9. Velina Guergueltcheva MD5,6,
  10. Ivailo Tournev MD, DSc6,
  11. Peter Van den Bergh MD7,
  12. Pavel Seeman MD8,
  13. Radim Mazanec MD9,
  14. Tomas Prochazka MD8,
  15. Ivo Kremensky MD, PhD7,
  16. Jana Haberlova MD8,
  17. Michael D. Weiss MD10,
  18. Vincent Timmerman PhD3,
  19. Thomas D. Bird MD10,11,
  20. Phillip F. Chance MD1,10

Article first published online: 26 APR 2004

DOI: 10.1002/ana.20094

Issue

Annals of Neurology

Annals of Neurology

Volume 55, Issue 5, pages 713–720, May 2004

Additional Information

How to Cite

Bennett, C. L., Shirk, A. J., Huynh, H. M., Street, V. A., Nelis, E., Van Maldergem, L., De Jonghe, P., Jordanova, A., Guergueltcheva, V., Tournev, I., Van den Bergh, P., Seeman, P., Mazanec, R., Prochazka, T., Kremensky, I., Haberlova, J., Weiss, M. D., Timmerman, V., Bird, T. D. and Chance, P. F. (2004), SIMPLE mutation in demyelinating neuropathy and distribution in sciatic nerve. Ann Neurol., 55: 713–720. doi: 10.1002/ana.20094

Author Information

  1. 1

    Department of Pediatrics, Division of Genetics and Developmental Medicine, University of Washington, Seattle, WA

  2. 2

    Department of Otolaryngology, University of Washington, Seattle, WA

  3. 3

    Molecular Genetics Department, Flanders Interuniversity Institute for Biotechnology, University of Antwerp, Antwerpen, Belgium

  4. 4

    Centre de Génétique Humaine, Institut de Pathologie et de Génétique, Loverval, Belgium

  5. 5

    Laboratory of Molecular Pathology, Sofia Medical University, Sofia, Bulgaria

  6. 6

    Department of Neurology, Sofia Medical University, Sofia, Bulgaria

  7. 7

    Service de Neurologie, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium

  8. 8

    Department of Child Neurology, 2nd School of Medicine, Charles University, Prague, Czech Republic

  9. 9

    Department of Neurology, 2nd School of Medicine, Charles University, Prague, Czech Republic

  10. 10

    Department of Neurology, University of Washington, Seattle, WA

  11. 11

    VA Puget Sound Health Care System, Seattle, WA

*Department of Pediatrics, Box 356320, University of Washington, Seattle, WA

Publication History

  1. Issue published online: 26 APR 2004
  2. Article first published online: 26 APR 2004
  3. Manuscript Revised: 4 FEB 2004
  4. Manuscript Accepted: 4 FEB 2004
  5. Manuscript Received: 3 NOV 2003

Funded by

  • NIH (National Institute of Neurological Disorders and Stroke)
  • Muscular Dystrophy Association
  • CMT Association
  • Sofia Medical University. Grant Number: 24/2001
  • National Science Fund of the Bulgarian Ministry of Education and Science. Grant Number: L1206/2002
  • Fund for Scientific Research (FWO–Flanders)
  • University of Antwerp
  • Medical Foundation Queen Elisabeth
  • Belgian Association for Neuro-Muscular Disease
  • Federal Office for Scientific, Technical and Cultural Affairs (OSTC/DWTC)
  • OSTC/DWTC
  • NATO/FWO
  • FWO
  • European Neurological Society (ENS)
  • Internal Grant Agency of Czech Ministry of Health. Grant Number: IGA NF6504
  • European Neurological Society (ENS)
  • Czech Ministry of School. Grant Number: VZ 111300003

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Abstract

Charcot–Marie–Tooth neuropathy type 1C (CMT1C) is an autosomal dominant demyelinating peripheral neuropathy caused by missense mutations in the small integral membrane protein of lysosome/late endosome (SIMPLE) gene. To investigate the prevalence of SIMPLE mutations, we screened a cohort of 152 probands with various types of demyelinating or axonal and pure motor or sensory inherited neuropathies. SIMPLE mutations were found only in CMT1 patients, including one G112S and one W116G missense mutations. A novel I74I polymorphism was identified, yet no splicing defect of SIMPLE is likely. Haplotype analysis of STR markers and intragenic SNPs linked to the gene demonstrated that families with the same mutation are unlikely to be related. The clustering of the G112S, T115N, and W116G mutations within five amino acids suggests this domain may be critical to peripheral nerve myelination. Electrophysiological studies showed that CMT1C patients from six pedigrees (n = 38) had reduced nerve conduction velocities ranging from 7.5 to 27.0m/sec (peroneal). Two patients had temporal dispersion of nerve conduction and irregularity of conduction slowing, which is unusual for CMT1 patients. We report the expression of SIMPLE in various cell types of the sciatic nerve, including Schwann cells, the affected cell type in CMT1C.

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