Phenotypes Associated with This Genotype

Genotype
MGI:3045972

• Allelic Composition: Aga^tm1Vk/Aga^tm1Vk
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * Black Swiss

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

mortality/aging

premature death ( J:91114 )

• the first spontaneous deaths occur at 10 months

• the average lifespan of homozygous mutant mice is 19 months

behavior/neurological

ataxia ( J:91114 )

• older homozygotes (>18 months) show a severe ataxic gait

impaired balance ( J:91114 )

• at 18 months or older, homozygotes exhibit great difficulty moving as well as poor balance

impaired coordination ( J:37022 , J:91114 )

• at the age of 5 to 10 months, homozygotes exhibit impaired neuromotor coordination (J:37022)

• at 18 months or older, homozygotes show impaired neuromotor coordination (J:91114)

impaired limb coordination ( J:91114 )

• at 18 months or older, homozygotes often drag their hind legs while walking

short stride length ( J:91114 )

• older homozygotes (>18 months) display short steps and often walk straddle-legged

cellular

abnormal lysosome morphology ( J:37022 , J:49386 , J:91114 )

• as early as 5-10 months, homozygotes exhibit a massive accumulation of aspartylglucosamine along with lysosomal vacuolization (J:37022)

• a strong accumulation of hypertrophic lysosomes is noted in the deep cerebellar nuclei whereas only relatively minor changes are observed in the hippocampus (J:49386)

• at >18 months, homozygotes show widely distributed lysosomal hypertrophy both in the CNS and in visceral organs (J:91114)

homeostasis/metabolism

abnormal urine homeostasis ( J:37022 , J:60272 )

• complete glycosylasparaginase deficiency leads to accumulation of aspartylglucosamine in tissues and urine (J:37022)

• adult homozygotes receiving i.v. injections of recombinant glycosylasparaginase rapidly restore aspartylglucosamine to normal levels in non-neuronal tissues (J:60272)

• a single AGA injection reduced the amount of aspartylglucosamine in liver and spleen by 90% and 80%, respectively (J:60272)

• AGU pathophysiologic features were reversed in non-neuronal tissues over a 2-week period of enzyme therapy (J:60272)

• glycosylasparaginase activity increased to 10% of that in wild-type brain tissue and the accumulation of aspartylglucosamine was decreased by 20% in total brain of treated mice (J:60272)

aspartylglucosaminuria ( J:37022 )

• complete glycosylasparaginase deficiency leads to accumulation of aspartylglucosamine in urine

colorless urine ( J:91114 )

• urine inside dilatated bladders is clear, not due to bacterial infections

liver/biliary system

multifocal hepatic necrosis ( J:91114 )

• many terminally ill homozygotes suffer from massive coagulative hepatic necrosis caused by bacterial infections

renal/urinary system

abnormal urine homeostasis ( J:37022 , J:60272 )

• complete glycosylasparaginase deficiency leads to accumulation of aspartylglucosamine in tissues and urine (J:37022)

• adult homozygotes receiving i.v. injections of recombinant glycosylasparaginase rapidly restore aspartylglucosamine to normal levels in non-neuronal tissues (J:60272)

• a single AGA injection reduced the amount of aspartylglucosamine in liver and spleen by 90% and 80%, respectively (J:60272)

• AGU pathophysiologic features were reversed in non-neuronal tissues over a 2-week period of enzyme therapy (J:60272)

• glycosylasparaginase activity increased to 10% of that in wild-type brain tissue and the accumulation of aspartylglucosamine was decreased by 20% in total brain of treated mice (J:60272)

aspartylglucosaminuria ( J:37022 )

• complete glycosylasparaginase deficiency leads to accumulation of aspartylglucosamine in urine

colorless urine ( J:91114 )

• urine inside dilatated bladders is clear, not due to bacterial infections

neurogenic bladder ( J:91114 )

• at >18 months, all aging homozygotes suffer from impaired bladder function

• as peripheral nerves remain unaffected, the "neurogenic bladder" phenotype is presumed to be secondary to the CNS defects

abnormal renal glomerulus morphology ( J:91114 )

• homozygotes display glomerular loss

renal interstitial fibrosis ( J:91114 )

• homozygotes exhibit interstitial fibrosis

abnormal kidney calyx morphology ( J:91114 )

• the caliceal mucosa is distended to one or two urothelial cells

hydronephrosis ( J:91114 )

• impaired bladder function and subsequent hydronephrosis are often associated with a reflux nephropathy

kidney atrophy ( J:91114 )

• renal parenchyma is thinned

renal tubule atrophy ( J:91114 )

• homozygotes display tubular atrophy

abnormal urinary bladder urothelium morphology ( J:91114 )

• the thickness of the urothelium varies with the degree of bladder distention, stretching to a thickness of two cells in the most distended area

distended urinary bladder ( J:37022 )

• a significant number of older male homozygotes have massively swollen bladders

anuria ( J:91114 )

• homozygotes fail to urinate, leading to a massive expansion of the bladder

nervous system

abnormal cerebellum morphology ( J:91114 )

• homozygotes display cerebellar damage, manifested as severe loss of Purkinje cells, intensive astrogliosis, and vacuolation of neurons in deep cerebellar nuclei

astrocytosis ( J:91114 )

• older mice (>18 months) show intensive astrogliosis

neurogenic bladder ( J:91114 )

• at >18 months, all aging homozygotes suffer from impaired bladder function

• as peripheral nerves remain unaffected, the "neurogenic bladder" phenotype is presumed to be secondary to the CNS defects

abnormal axon morphology ( J:37022 )

• at 5-10 months, homozygotes exhibit axonal swelling in the gracile nucleus

neurodegeneration ( J:91114 )

• in older homozygotes (>18 months), severe neuronal vacuolation is often associated with neuronal loss

• neuronal vacuolation is pronounced in the lateral thalamic nuclei, medullary reticular nuclei, vestibular nuclei, inferior olivary complex, and deep cerebellar nuclei

• severe vacuolation of cells in the vestibular and cochlear nuclei may contribute to the impairment of neuromotor coordination

Purkinje cell degeneration ( J:91114 )

• unlike AGU patients, where loss of Purkinje cells is scattered, homozygotes display widespread loss of Purkinje cells

integument

disheveled coat ( J:91114 )

• at ~5 months, homozygotes start to exhibit a general scruffiness, recognizable from their disheveled coat

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
aspartylglucosaminuria		DOID:0050461	OMIM:208400	J:37022