C-terminal deletion of the atrophin-1 protein results in growth retardation but not neurodegeneration in mice.

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Dentatorubral-pallidoluysian atrophy (DRPLA ) is a dominant hereditary neurodegenerative disorder caused by the expansion of a poly-glutamine (poly-Q ) repeat in Atrophin-1 protein . Ectopic expression of a poly-Q expanded human Atrophin-1 is sufficient to induce DRPLA phenotypes in mice . However , it is still unclear whether the dominant effect of poly-Q expansion is due to the functional interference with wild-type Atrophin-1 proteins , which exist in both patients and transgenic mice . Here we report the generation and analysis of an Atrophin-1 targeting allele that expresses a truncated protein lacking both the poly-Q repeat and following C-terminal peptides . Homozygous mutants exhibit growth retardation and progressive male infertility , but no obvious signs of neurodegeneration . Moreover , the mutant allele neither blocked nor enhanced the neurodegenerative phenotypes caused by a poly-Q expanded transgene . These results support the model that poly-Q expanded Atrophin-1 proteins cause DRPLA in a manner independent of any functional interaction with wild-type Atrophin-1 proteins .