International Mammalian Genome Society

The 15th International Mouse Genome Conference (2001)


Dr. Thomas Schmitt-John
University of Bielefeld
Universitätsstrasse 25
33615 Bielefeld, Germany

Co-Authors: 1) Ulbrich, M, 2) Schmidt, VC, 1) Ronsiek, M, 1) Mußmann, A, 2) Bartsch, J-W., 2) Augustin, M, 1) Jockusch, H.
Institutions: 1) University of Bielefeld, 2) Ingenium AG, Dept. Genomics

The autosomal recessive mutation wobbler of the mouse (phenotype WR; genotype wr/wr) causes motoneuron degeneration and a defect in spermatogenesis. In inter- and backcrosses with M. m. castaneus strain CAST/EI we have observed a variability in the severity of neurological symptoms. Approximately 15% of all (wr/wr) CAST/B6 hybrids expressed an aggravated neuromuscular phenotype with strongly affected hindlimbs. Thus we infer the existence of modifying alleles within the CAST/EI strain. These modified wobbler mice (WR-MOD) exhibit an advanced neurodegeneration in the ventral horn from cervical to lumbal spinal cord, paralleled by a strong astrogliosis and increased levels of acetylcholine receptor a-subunit mRNA in hindlib muscles. Genetic analysis, using 68 polymorphic autosomal markers in a whole genome scan, revealed a major modifier gene locus on chromosome 14, located in a 3.6 cM intervall between D14MIT124 and D14MIT103. We produced a partially consomic strain to confirm our mapping data. The critical interval contains the Retinoblastoma gene (Rb1), esterase 10 gene (Es10), serotonin receptor (Htr2a), transforming growth factor b1 induced gene (Tgfb1i) and protocadherin genes 8 & 9 (Pcd 8, Pcd9).

These findings provide access to modifier genes, the human counterparts of which may be responsible for the variable expression of hereditary spinal muscular atrophies in humans.

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