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Abnormalities of germ cell maturation and sertoli cell cytoskeleton in androgen receptor 113 CAG knock-in mice reveal toxic effects of the mutant protein.

An unresolved question in the study of the polyglutamine neurodegenerative disorders is the extent to which partial loss of normal function of the mutant protein contributes to the disease phenotype. To address this, we studied Kennedy disease, a degenerative disorder of lower motor neurons caused by a CAG/glutamine expansion in the androgen receptor (Ar) gene. Signs of partial androgen insensitivity, including testicular atrophy and decreased fertility, are common in affected males, although the underlying mechanisms are not well understood. Here, we describe a knock-in mouse model that reproduces the testicular atrophy, diminished fertility, and systemic signs of partial androgen insensitivity that occur in Kennedy disease patients. Using this model, we demonstrate that the testicular pathology in this disorder is distinct from that mediated by loss of AR function. Testes pathology in 113 CAG knock-in mice was characterized by morphological abnormalities of germ cell maturation, decreased solubility of the mutant AR protein, and alterations of the Sertoli cell cytoskeleton, changes that are distinct from those produced by AR loss-of-function mutation in testicular feminization mutant mice. Our data demonstrate that toxic effects of the mutant protein mediate aspects of the Kennedy disease phenotype previously attributed to a loss of AR function.

Pubmed ID: 16400023


  • Yu Z
  • Dadgar N
  • Albertelli M
  • Scheller A
  • Albin RL
  • Robins DM
  • Lieberman AP


The American journal of pathology

Publication Data

January 9, 2006

Associated Grants

  • Agency: NCI NIH HHS, Id: 5P30 CA46592
  • Agency: NIDDK NIH HHS, Id: DK20572
  • Agency: NIA NIH HHS, Id: K08 AG024758
  • Agency: NICHD NIH HHS, Id: U54 HD28934

Mesh Terms

  • Age Factors
  • Animals
  • Cell Differentiation
  • Cytoskeleton
  • Disease Models, Animal
  • Female
  • Gene Expression
  • Germ Cells
  • Humans
  • Immunohistochemistry
  • In Situ Nick-End Labeling
  • Infertility
  • Male
  • Mice
  • Mice, Mutant Strains
  • Muscular Atrophy, Spinal
  • Mutation
  • Receptors, Androgen
  • Sertoli Cells
  • Trinucleotide Repeat Expansion