Phenotypes Associated with This Genotype

Genotype
MGI:3614453

• Allelic Composition: Ar^tm4(AR)Dmr/Y
• Genetic Background: involves: 129S1/Sv * C57BL/6J

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

mortality/aging

premature death ( J:114552 )

♂ • ~80% of hemizygous mutant males unexpectedly die at 2-4 months of age; not observed in heterozygous mutant females

♂ • 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

♂ • testosterone treatment of aged, castrated mutant males results in death of 60% of mutant versus only ~20% of wild-type males within 6 months

♂ • mutant males surviving past 20 weeks (10%-20%) are protected from early death by progressive testicular atrophy and reduced testosterone production

reproductive system

abnormal testis morphology ( J:104360 )

♂

abnormal seminiferous tubule morphology ( J:114552 )

♂ • hemizygous mutant males euthanized at 24 months of age show complete loss of normal cellular elements within the seminiferous tubules

abnormal Sertoli cell morphology ( J:104360 )

♂ • diminished branching of the cytoskeleton in Sertoli cells

decreased testis weight ( J:104360 )

♂ • testes weigh only about half that of wild-type

testicular atrophy ( J:104360 , J:114552 )

♂ • age-dependent testicular atrophy (J:104360)

♂ • hemizygous mutant males euthanized at 24 months of age display atrophic testes (J:114552)

abnormal spermatogenesis ( J:104360 )

♂ • abnormal germ cell maturation is seen at 12-20 weeks of age but not at 11 weeks or younger ages

oligozoospermia ( J:104360 )

♂ • about 7-fold decrease of epididymal sperm

reduced male fertility ( J:104360 , J:114552 )

♂ • 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)

homeostasis/metabolism

abnormal blood homeostasis ( J:114552 )

♂ • prior to death, mutant males are azotemic and hyperkalemic, consistent with acute urinary tract obstruction

♂ • however, sodium and chloride levels remain unaffected

increased circulating creatinine level ( J:114552 )

♂ • moribund mutant males exhibit significantly increased creatinine levels

increased blood urea nitrogen level ( J:114552 )

♂ • moribund mutant males exhibit significantly increased blood urea nitrogen

decreased circulating testosterone level ( J:114552 )

♂ • hemizygous mutant males that survive to 8-10 months show a 80% reduction in serum testosterone levels relative to wild-type males

♂ • however, longer survival does not correlate with lower serum testosterone levels at 10-12 weeks of age

decreased circulating follicle stimulating hormone level ( J:104360 )

♂

increased circulating luteinizing hormone level ( J:104360 )

♂

increased circulating potassium level ( J:114552 )

♂ • moribund mutant males exhibit significantly increased potassium levels

decreased urine major urinary protein level ( J:104360 )

♂ • lower levels of urinary MUPs, the pheromone-binding proteins that contribute to normal mating behavior

renal/urinary system

decreased urine major urinary protein level ( J:104360 )

♂ • lower levels of urinary MUPs, the pheromone-binding proteins that contribute to normal mating behavior

distended urinary bladder ( J:114552 )

♂ • at necropsy, mutant males display significantly distended bladders with no evidence of physical obstruction

behavior/neurological

decreased grip strength ( J:114552 )

♂ • as early as 8 weeks of age, hemizygous mutant males show significantly reduced forelimb grip-strength relative to wild-type males

♂ • reduction in grip strength is glutamine length-dependent, as adult Ar^tm3(AR)Dmr males with a targeted insertion of 48 CAG repeats show normal forelimb strength relative to wild-type males

♂ • surgical castration partially restores grip-strength, suggesting that this deficit is androgen-dependent

♂ • testosterone-treated, castrated mutant males display forelimb grip strength similar to that of noncastrated mutant males

growth/size/body

decreased body size ( J:114552 )

♂ • at 10-90 weeks of age, hemizygous mutant males are smaller than wild-type males

decreased body weight ( J:114552 )

♂ • at 10-90 weeks of age, hemizygous mutant males show decreased body weights relative to wild-type males

♂ • surgical castration at 4-5 weeks of age causes a slight further reduction in mean body mass in mutant males

muscle

abnormal skeletal muscle fiber morphology ( J:114552 )

♂

skeletal muscle fiber atrophy ( J:114552 )

♂ • at 3-5 months of age, mutant hind-limb skeletal muscles display grouped atrophic, angulated fibers suggesting neurogenic atrophy

increased variability of skeletal muscle fiber size ( J:114552 )

♂ • at 3-5 months of age, mutant hind-limb skeletal muscles display significant variation in fiber size

centrally nucleated skeletal muscle fibers ( J:114552 )

♂ • at 3-5 months of age, mutant hind-limb skeletal muscles display internally placed nuclei

abnormal muscle electrophysiology ( 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

♂ • 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

♂ • 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)

♂ • 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

impaired muscle relaxation ( 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

♂ • nonsustained myotonia in the levator ani/bulbocavernosus muscles leads to functional urinary tract obstruction and death

muscle weakness ( 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

progressive muscle weakness ( J:114552 )

♂

myopathy ( J:114552 )

♂ • as early as 10-15 weeks, mutant hind-limb muscles show rounded muscle fibers with internal nuclei, indicating myopathy

♂ • 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

nervous system

abnormal spinal cord morphology ( J:114552 )

♂ • hemizygous mutant males show neuronal intranuclear inclusions in spinal cord at 24 months but not at 3-5 months of age

motor neuron degeneration ( 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

endocrine/exocrine glands

abnormal testis morphology ( J:104360 )

♂

abnormal seminiferous tubule morphology ( J:114552 )

♂ • hemizygous mutant males euthanized at 24 months of age show complete loss of normal cellular elements within the seminiferous tubules

abnormal Sertoli cell morphology ( J:104360 )

♂ • diminished branching of the cytoskeleton in Sertoli cells

decreased testis weight ( J:104360 )

♂ • testes weigh only about half that of wild-type

testicular atrophy ( J:104360 , J:114552 )

♂ • age-dependent testicular atrophy (J:104360)

♂ • hemizygous mutant males euthanized at 24 months of age display atrophic testes (J:114552)

cellular

oligozoospermia ( J:104360 )

♂ • about 7-fold decrease of epididymal sperm

abnormal cell cytoskeleton morphology ( J:104360 )

♂ • diminished branching of the cytoskeleton in Sertoli cells

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
NOT	androgen insensitivity syndrome	DOID:4674	OMIM:300068	J:104360
Kennedy's disease		DOID:0060161	OMIM:313200	J:104360 , J:114552