A missense mutation in Tbce causes progressive motor neuronopathy in mice

Abstract

Mice 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 birth. 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 orthologous. 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.

KBP is essential for axonal structure, outgrowth and maintenance in zebrafish, providing insight into the cellular basis of Goldberg-Shprintzen syndrome

“…For example, stathmin controls the availability of soluble tubulin molecules (Fletcher and Rorth, 2007); the tubulin specific chaperone e (tbce) ensures proper folding of ␣-tubulin and regulates tubulin heterodimer formation (Kortazar et al, 2007); SCG10 regulates the dynamics of microtubules in growing axons (Belmont and Mitchison, 1996;Riederer et al, 1997;Suh et al, 2004); and microtubule-associated proteins (MAPs), such as tau, have a number of important functions. In fact, tbce mutant mice have a somewhat similar phenotype to our kbp mutant, with disruption to axonal microtubules and subsequent axonal degeneration (Martin et al, 2002). Further biochemical studies will be required to elucidate the mechanisms by which KBP regulates the axonal cytoskeleton.…”

Inhibition of Chaperone Activity Is a Shared Property of Several Cu,Zn-Superoxide Dismutase Mutants That Cause Amyotrophic Lateral Sclerosis

“…Additional genes are being identified (7)(8)(9). Animal studies suggest more gene mutations that may cause human ALS, including neurofilaments (10), dynein (11), dynamitin (12), tubulin chaperon (13,14), and vegf (15).…”

Genetic disorders involving molecular-chaperone genes: A perspective

“…This anomaly could be corrected by transgenic complementation with a wild-type gene. 49 The conclusion was that the TbcE gene, and consequently its protein product, cofactor E, play a key role in microtubule biogenesis and stability in motor neurons. Most importantly, when cofactor E is altered, motor neuron disease ensues.…”

“…A missense mutation in the gene TbcE, encoding cofactor E in mice, has been implicated as a cause of progressive motor neuronopathy (PMN). 49,50 Examination of the sciatic and phrenic nerves of affected mice, by electron microscopy, showed a scarcity of microtubules. This anomaly could be corrected by transgenic complementation with a wild-type gene.…”

“…49 These animals serve as a model for studies pertinent to the autosomal recessive proximal spinal muscular atrophy (SPM) of children. A missense mutation in the gene TbcE, encoding cofactor E in mice, has been implicated as a cause of progressive motor neuronopathy (PMN).…”