Mouse Genome Informatics
ot
    Artm4(AR)Dmr/Y
involves: 129S1/Sv * C57BL/6J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
       
mortality/aging
• ~80% of hemizygous mutant males unexpectedly die at 2-4 months of age; not observed in heterozygous mutant females (J:114552)
• early death is glutamine-length dependent and completely prevented by surgical castration, as all N2 mutant males castrated at 5 weeks survive for 18 months (J:114552)
• testosterone treatment of aged, castrated mutant males results in death of 60% of mutant versus only ~20% of wild-type males within 6 months (J:114552)
• mutant males surviving past 20 weeks (10%-20%) are protected from early death by progressive testicular atrophy and reduced testosterone production (J:114552)

reproductive system
• hemizygous mutant males euthanized at 24 months of age show complete loss of normal cellular elements within the seminiferous tubules (J:114552)
• diminished branching of the cytoskeleton in Sertoli cells (J:104360)
• testes weigh only about half that of wild-type (J:104360)
• age-dependent testicular atrophy (J:104360)
• hemizygous mutant males euthanized at 24 months of age display atrophic testes (J:114552)
• abnormal germ cell maturation is seen at 12-20 weeks of age but not at 11 weeks or younger ages (J:104360)
• about 7-fold decrease of epididymal sperm (J:104360)
• multiple attempted matings yielded only 2 litters, sired by males younger than 10 weeks of age (J:104360)
• hemizygous mutant males show reduced fertility due to the toxicity conferred by the expanded glutamine tract (J:114552)

endocrine/exocrine glands
• hemizygous mutant males euthanized at 24 months of age show complete loss of normal cellular elements within the seminiferous tubules (J:114552)
• diminished branching of the cytoskeleton in Sertoli cells (J:104360)
• testes weigh only about half that of wild-type (J:104360)
• age-dependent testicular atrophy (J:104360)
• hemizygous mutant males euthanized at 24 months of age display atrophic testes (J:114552)

homeostasis/metabolism
• prior to death, mutant males are azotemic and hyperkalemic, consistent with acute urinary tract obstruction (J:114552)
• however, sodium and chloride levels remain unaffected (J:114552)
• moribund mutant males exhibit significantly increased creatinine levels (J:114552)
• moribund mutant males exhibit significantly increased blood urea nitrogen (J:114552)
• hemizygous mutant males that survive to 8-10 months show a 80% reduction in serum testosterone levels relative to wild-type males (J:114552)
• however, longer survival does not correlate with lower serum testosterone levels at 10-12 weeks of age (J:114552)
• moribund mutant males exhibit significantly increased potassium levels (J:114552)
• lower levels of urinary MUPs, the pheromone-binding proteins that contribute to normal mating behavior (J:104360)

renal/urinary system
• lower levels of urinary MUPs, the pheromone-binding proteins that contribute to normal mating behavior (J:104360)
• at necropsy, mutant males display significantly distended bladders with no evidence of physical obstruction (J:114552)

behavior/neurological
• as early as 8 weeks of age, hemizygous mutant males show significantly reduced forelimb grip-strength relative to wild-type males (J:114552)
• reduction in grip strength is glutamine length-dependent, as adult Artm3(AR)Dmr males with a targeted insertion of 48 CAG repeats show normal forelimb strength relative to wild-type males (J:114552)
• surgical castration partially restores grip-strength, suggesting that this deficit is androgen-dependent (J:114552)
• testosterone-treated, castrated mutant males display forelimb grip strength similar to that of noncastrated mutant males (J:114552)

growth/size
• at 10-90 weeks of age, hemizygous mutant males are smaller than wild-type males (J:114552)
• at 10-90 weeks of age, hemizygous mutant males show decreased body weights relative to wild-type males (J:114552)
• surgical castration at 4-5 weeks of age causes a slight further reduction in mean body mass in mutant males (J:114552)

muscle
• at 3-5 months of age, mutant hind-limb skeletal muscles display grouped atrophic, angulated fibers suggesting neurogenic atrophy (J:114552)
• at 3-5 months of age, mutant hind-limb skeletal muscles display significant variation in fiber size (J:114552)
• at 3-5 months of age, mutant hind-limb skeletal muscles display internally placed nuclei (J:114552)
• by 3-5 months of age, all hemizygous mutant males exhibit abnormal electrical activity in skeletal muscle indicative of both myopathic and neurogenic changes, as shown by needle electromyography (J:114552)
• abnormal insertional activity occurs more frequently in the levator ani/bulbocavernosus muscles than in hind-limb muscles of mutant males and is absent in either muscle group of wild-type males (J:114552)
• abnormal spontaneous activity indicative of denervation occurs in all mutant males in both the levator ani/bulbocavernosus and hind-limb muscles, and consists of sustained and unsustained regularly firing positive waves occurring at a low frequency (<30 Hz) (J:114552)
• abnormal spontaneous activity occurs more frequently in levator ani/bulbocavernosus muscles (~50% of needle insertions) than in hind-limb muscles (~25% of needle insertions) and is not observed in wild-type muscles (J:114552)
• needle electromyography of mutant hind-limb and levator ani/bulbocavernosus muscles shows abnormal electrical activity, with positive waves oscillating in amplitude for >300 ms, indicating myotonic discharges in skeletal muscle of the lower urinary tract (J:114552)
• nonsustained myotonia in the levator ani/bulbocavernosus muscles leads to functional urinary tract obstruction and death (J:114552)
• hemizygous mutant males develop androgen- and and glutamine length-dependent neuromuscular weakness associated with early myopathic and neurogenic skeletal muscle pathology and late development of neuronal intranuclear inclusions in spinal neurons (J:114552)
• as early as 10-15 weeks, mutant hind-limb muscles show rounded muscle fibers with internal nuclei, indicating myopathy (J:114552)
• initial skeletal myopathy includes AR and ubiquitin immunoreactive intranuclear inclusions, increased expression of myogenin and acetylcholine receptor alpha-subunit mRNAs, and abnormal spontaneous and insertional electrical activity evident by 3-5 months (J:114552)

nervous system
• hemizygous mutant males show neuronal intranuclear inclusions in spinal cord at 24 months but not at 3-5 months of age (J:114552)
• at 3-5 months of age, hind-limb muscles of mutant males display significantly reduced expression of muscle-derived neurotrophic factors known to affect motor neuron survival (J:114552)

Mouse Models of Human Disease
OMIM IDRef(s)
NOT Androgen Insensitivity Syndrome; AIS 300068 J:104360
Spinal and Bulbar Muscular Atrophy, X-Linked 1; SMAX1 313200 J:104360 , J:114552