Nature Genetics
32, 443 - 447 (2002)
Published online: 21 October 2002; | doi:10.1038/ng1016
A missense mutation in Tbce causes progressive motor neuronopathy in miceNatalia Martin1, Jean Jaubert1, Pierre Gounon2, Eduardo Salido3, Georg Haase4, Marek Szatanik1
& Jean-Louis Guénet11
Unité de Génétique des Mammifères, Institut Pasteur, 25 Rue du Docteur Roux, F-75724 Paris Cedex 15, France. 2
Station centrale de Microscopie électronique, Institut Pasteur, Paris, France. 3
Unidad de Investigacion, Hospital Universitario Canarias, Tenerife, Spain. 4
Institut National de la Santé et de la Recherche Médicale, Institut de Biologie du Développement de Marseille (Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale and Université de la Méditerranée), Campus de Luminy, Marseille, France.
Correspondence should be addressed to Jean-Louis Guénet guenet@pasteur.frMice that are homozygous with respect to the progressive motor neuronopathy (pmn) mutation (chromosome 13) develop a progressive caudio-cranial degeneration of their motor axons from the age of two weeks and die four to six weeks after birth1. The mutation is fully penetrant, and expressivity does not depend on the genetic background. Based on its pathological features, the pmn mutation has been considered an excellent model for the autosomal recessive proximal childhood form of spinal muscular atrophy (SMA). Previously, we demonstrated that the genes responsible for these disorders were not orthologous2,
3. Here, we identify the pmn mutation as resulting in a Trp524Gly substitution at the last residue of the tubulin-specific chaperone e (Tbce) protein that leads to decreased protein stability. Electron microscopy of the sciatic and phrenic nerves of affected mice showed a reduced number of microtubules, probably due to defective stabilization. Transgenic complementation with a wildtype Tbce cDNA restored a normal phenotype in mutant mice. Our observations indicate that Tbce is critical for the maintenance of microtubules in mouse motor axons, and suggest that altered function of tubulin cofactors might be implicated in human motor neuron diseases.
|
