Crumbling microtubules, those slender filaments that aid a variety of cellular processes from cell division to vesicle trafficking, could lead to motor neuron disease. This idea is put forth in today’s online Nature Genetics by Jean-Louis Guénet of the Pasteur Institute in Paris, and colleagues at the Canary Islands University Hospital, Tenerife, Spain, and the Université de la Méditerranée, Marseille, France.

First author Natalia Martin and coworkers used polymerase chain reactions to amplify mouse genes that may harbor the progressive motor neuronopathy (pmn) mutation. Mice homozygous for this lesion rapidly lose caudiocranial motor axons and die within a few weeks of birth. Guénet et al. had previously mapped the mutation to a small region on chromosome 13, and in this latest they showed that the phenotype is the result of a single thymidine to guanine transversion, which leads to the substitution of a glycine for a tryptophan.

The transversion occurs in the very last codon of the gene for tubulin-specific chaperone e (Tbce), which is thought to play an important role in the proper folding of α-tubulin subunits, and hence in the growth of microtubules. Pmn mice, the authors show, have much less of the chaperone than wild-type animals, and the severity of the phenotype correlates with loss of microtubules. Electron microscopy in one-week-old mice shows a dramatic loss of microtubules in those animals with the most advanced symptoms.

This study suggests that a misbehaving chaperone may have disastrous consequences. A single chaperone may even wreak completely different kinds of havoc depending on which protein interactions malfunction, according to a letter from The HRD/Autosomal Recessive Kenny-Caffey Syndrome Consortium in the same issue of Nature Genetics. The consortium comprises researchers from Israel, Belgium, UK, Saudi Arabia, USA, and Kuwait. It has traced the mutations responsible for HRD (also called Sanjad-Sakati syndrome), a rare congenital form of hypoparathyroidism that leads to mental retardation, facial distortion, and growth failure, as well as mutations leading to Kenny-Caffey syndrome, which is marked by osteosclerosis and susceptibility to recurring bacterial infections. Both of these disorders have previously been mapped to chromosome 1 and seem to share a common gene.

This gene codes for the human Tbce, and phenotypes result from several different mutations, including a 12 base-pair deletion that occurred in all affected Middle Eastern patients tested and a 2 base-pair deletion accompanied by a single adenine to thymine transversion in two Belgian siblings. These mutations are predicted to result in the loss of amino acids in the α-tubulin binding domain (12 bp deletion), or premature termination of the protein at residue 48 (2 bp deletion) or 370 (transversion). While the glycine to tryptophan mutation in the pmn mice resulted in loss of Tbce due to instability, the human mutant proteins are reported to be stable when overexpressed, raising the possibility, according to the consortium, that they may retain residual activity. The latter may explain why the human phenotype, though severe, is not lethal.-Tom Fagan.

References: Martin N, Jaubert J, Gounon P, Salido E, Haase G, Szatanik M, Guénet J-L. A missense mutation in Tbce causes progressive motor neuronopathy in mice. Nature Genetics. 2002 October 21. Abstract

Parvari R, Hershkovitz E, Grossman N, Gorodischer R, Loeys B, Zecic A, Mortier G, Gregory S, Sharony R, Kambouris M, Sakati N, Meyer BF, Al Aqeel AI, Al Humaidan AK, Al Zanhrani F, Al Swaid A, Al Othman J, Diaz GA, Weiner R, Khan KTS, Gordon R, Gelb BD. The HRD/Autosomal Recessive Kenny-Caffey Syndrome Consortium. Mutation of TBCE causes hypoparathyroidism-retardation-dysmorphism and autosomal recessive Kenny-Caffey syndrome. Nature Genetics. 2002 October 21. Abstract

Guénet et al. Abstract

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  1. This paper mixes well with the dynamitin paper that was published some time back. Also, its chaperone function is definitely interesting. The only other chaperones studied in ALS are HSP70 and CCS. However, no mutations in any chaperones have been identified before. The HSP70 knockout and the CCS knockout mice also showed no change in phenotype when crossed to the SOD1 mice.

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References

Paper Citations

  1. . A missense mutation in Tbce causes progressive motor neuronopathy in mice. Nat Genet. 2002 Nov;32(3):443-7. PubMed.
  2. . Cloning of two tryptophan hydroxylase genes expressed in the diencephalon of the developing zebrafish brain. Gene Expr Patterns. 2002 Dec;2(3-4):251-6. PubMed.
  3. . Therapeutic potential of cannabinoids in CNS disease. CNS Drugs. 2003;17(3):179-202. PubMed.

Further Reading

Papers

  1. . A missense mutation in Tbce causes progressive motor neuronopathy in mice. Nat Genet. 2002 Nov;32(3):443-7. PubMed.
  2. . Cloning of two tryptophan hydroxylase genes expressed in the diencephalon of the developing zebrafish brain. Gene Expr Patterns. 2002 Dec;2(3-4):251-6. PubMed.
  3. . Therapeutic potential of cannabinoids in CNS disease. CNS Drugs. 2003;17(3):179-202. PubMed.

Primary Papers

  1. . A missense mutation in Tbce causes progressive motor neuronopathy in mice. Nat Genet. 2002 Nov;32(3):443-7. PubMed.
  2. . Cloning of two tryptophan hydroxylase genes expressed in the diencephalon of the developing zebrafish brain. Gene Expr Patterns. 2002 Dec;2(3-4):251-6. PubMed.
  3. . Therapeutic potential of cannabinoids in CNS disease. CNS Drugs. 2003;17(3):179-202. PubMed.