Journal Article

A mouse model of spinal and bulbar muscular atrophy

Patrick McManamny, Hun S. Chy, David I. Finkelstein, Rebecca G. Craythorn, Peter J. Crack, Ismail Kola, Surindar S. Cheema, Malcolm K. Horne, Nigel G. Wreford, Moira K. O'Bryan, David M. de Kretser and John R. Morrison

in Human Molecular Genetics

Volume 11, issue 18, pages 2103-2111
Published in print September 2002 | ISSN: 0964-6906
Published online September 2002 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/11.18.2103
A mouse model of spinal and bulbar muscular atrophy

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Spinal and bulbar muscular atrophy (SBMA) is an adult-onset motor neuron disease, caused by the expansion of a trinucleotide repeat (TNR) in exon 1 of the androgen receptor (AR) gene. This disorder is characterized by degeneration of motor and sensory neurons, proximal muscular atrophy, and endocrine abnormalities, such as gynecomastia and reduced fertility. We describe the development of a transgenic model of SBMA expressing a full-length human AR (hAR) cDNA carrying 65 (AR65) or 120 CAG repeats (AR120), with widespread expression driven by the cytomegalovirus promoter. Mice carrying the AR120 transgene displayed behavioral and motor dysfunction, while mice carrying 65 CAG repeats showed a mild phenotype. Progressive muscle weakness and atrophy was observed in AR120 mice and was associated with the loss of α-motor neurons in the spinal cord. There was no evidence of neurodegeneration in other brain structures. Motor dysfunction was observed in both male and female animals, showing that in SBMA the polyglutamine repeat expansion causes a dominant gain-of-function mutation in the AR. The male mice displayed a progressive reduction in sperm production consistent with testis defects reported in human patients. These mice represent the first model to reproduce the key features of SBMA, making them a useful resource for characterizing disease progression, and for testing therapeutic strategies for both polyglutamine and motor neuron diseases.

Journal Article.  6216 words.  Illustrated.

Subjects: Genetics and Genomics

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