International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA


Schmitt-John T, Drepper C, Hahn P, Mussmann A, Ulbrich M, Beckers J, Jockusch H

Univerity of Bielefeld, Bielefeld, Germany

The recessive wobbler (wr, Chr 11; phenotype WR) mutation of the mouse causes a spinal muscular atrophy (SMA), a progressive degeneration of motoneurons which secondarily leads to an atrophy of skeletal muscles. The wobbler mouse serves as an animal model for human SMAs and amyotrophic lateral sclerosis (ALS). In addition to the neurological effect the mutation causes a spermiogenesis defect.

Here we report on a further narrowing down of the wr-critical chromosomal interval and the detailed characterization of novel candidate genes for wobbler. A previously reported inversion [1] between mouse and man was not confirmed. In one of the characterized genes a single base mutation was identified, making it a hot candidate.

An extensive microarray based expression profiling of WR CNS mainly revealed secondary consequences of neurodegeneration, astro- and microgliosis, but also surprising similarities to expression alterations in the CNS of human Tay Sachs patients [2].

In crosses of the standard C57BL/6J stock with M. m. castaneus we observed a wide variation of the severity of the neurological phenotype. QTL mapping was performed and a major modifier locus (wrmod1) for the neurological WR phenotype was mapped to Chr 14 [3]. An M. m. castaneus-specific polymorphism within the middle neurofilament gene Nfm affecting a highly conserved KSP-phosphorylation site was detected. This might be responsible for the aggravated neurological WR* phenotype. An altered expression of the Nfm gene was observed in expression profiling of WR spinal cords. NF-M deposits were found in the pericarya of WR* neurons and axonal calibers were found to be reduced. We conclude that NF-M is involved in the wobbler pathogenesis.

Supported by DFG (SCHM1276/1) and NGFN (Xpress).

[1] Fuchs et al. (2002) BMC Genetics 3:14.

[2] Myerowitz et al. (2002) Human Molecular Genetics 11 : 1343-1350

[3] Ulbrich et al. (2002) NeuroReport 13: 535-539.

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