Human Molecular Genetics, 2003, Vol. 12, No. 15 1917-1925
DOI: 10.1093/hmg/ddg198
© 2003 Oxford University Press
Hereditary sensory neuropathy is caused by a mutation in the delta subunit of the cytosolic chaperonin-containing t-complex peptide-1 (Cct4 ) gene
1Division of Clinical Neurology and Department of Molecular Pathogenesis, Institute of Neurology, Queen Square, London, WC1N 3BG, UK, 2McLaughlin Research Institute, 1520 23rd Street South, Great Falls, Montana 59405, USA, 3Division of Paediatric Neurology, Department of Paediatrics, College of Medicine, PO Box 2925, King Saudi University, Saudi Arabia, 4Molecular Genetics Department, Flanders Interuniversity Institute for Biotechnology (VIB), University of Antwerp (UIA), Belgium, 5Institute of Medical Biology and Human Genetics, Karl-Franzens University, Graz, Austria and 6Department of Neurosciences, Ophthalmology and Genetics, Section of Medical Genetics, University of Genova, Via Benedetto XV, 6-16132 Genova, Italy
Received February 7, 2003; Accepted June 4, 2003
A spontaneous autosomal recessive mutation was identified in the Sprague–Dawley rat strain with an early onset sensory neuropathy. The main clinical features of the mutation (mutilated foot, mf ), detectable shortly after birth, include ataxia, insensitivity to pain and foot ulceration. The pathological features include a severe reduction in the number of sensory ganglia and fibres. This mutant is therefore an excellent model for human hereditary sensory neuropathies. Here, we demonstrate that the mf locus maps to the distal end of rat chromosome 14, a region syntenic to human 2p13–p16 and proximal mouse 11. Sequence analysis of four candidate genes in this interval revealed a 1349G>A mutation in the chaperonin (delta) subunit 4 (Cct4) gene associated with the mf mutant. This change resulted in the substitution of a highly conserved cysteine for tyrosine at amino acid 450. Although we did not identify a mutation in the human CCT4 gene in a set of HSN patients, this result clearly demonstrates the pathological consequences of a defect in Cct4, a subunit of CCT (cytosolic chaperonin-containing t-complex peptide-1), involved in folding tubulin, actin and other cytosolic proteins. This is the first report of a mutation in a molecular chaperonin causing a hereditary neuropathy and raises the possibility that mis-folding proteins may be a cause of this group of neuropathies.
* To whom correspondence should be addressed. Tel: +44 2078373611, ext. 3457; Fax: +44 2078132126; Email: m.reilly{at}ion.ucl.ac.uk
Present address: Department of Medical Genetics, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei 100, Taiwan.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  A Bouhouche, A Benomar, N Bouslam, T Chkili, and M Yahyaoui Mutation in the epsilon subunit of the cytosolic chaperonin-containing t-complex peptide-1 (Cct5) gene causes autosomal recessive mutilating sensory neuropathy with spastic paraplegia J. Med. Genet., May 1, 2006; 43(5): 441 - 443. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Lazar, C. Moreno, H. J. Jacob, and A. E. Kwitek Impact of genomics on research in the rat Genome Res., December 1, 2005; 15(12): 1717 - 1728. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. McCampbell, D. Truong, D. C. Broom, A. Allchorne, K. Gable, R. G. Cutler, M. P. Mattson, C. J. Woolf, M. P. Frosch, J. M. Harmon, et al. Mutant SPTLC1 dominantly inhibits serine palmitoyltransferase activity in vivo and confers an age-dependent neuropathy Hum. Mol. Genet., November 15, 2005; 14(22): 3507 - 3521. [Abstract] [Full Text] [PDF]
|
|