Mouse Genome Informatics
hm
    Agatm1Vk/Agatm1Vk
involves: 129S1/Sv * 129X1/SvJ * Black Swiss
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
       
mortality/aging
• the first spontaneous deaths occur at 10 months
• the average lifespan of homozygous mutant mice is 19 months

behavior/neurological
• older homozygotes (>18 months) show a severe ataxic gait
• at 18 months or older, homozygotes exhibit great difficulty moving as well as poor balance
• 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)
• at 18 months or older, homozygotes often drag their hind legs while walking
• older homozygotes (>18 months) display short steps and often walk straddle-legged

cellular
• 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
• 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)
• complete glycosylasparaginase deficiency leads to accumulation of aspartylglucosamine in urine
• urine inside dilatated bladders is clear, not due to bacterial infections
• homozygotes exhibit interstitial fibrosis

liver/biliary system
• many terminally ill homozygotes suffer from massive coagulative hepatic necrosis caused by bacterial infections

renal/urinary system
• 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)
• complete glycosylasparaginase deficiency leads to accumulation of aspartylglucosamine in urine
• urine inside dilatated bladders is clear, not due to bacterial infections
• homozygotes exhibit interstitial fibrosis
• 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
• homozygotes display glomerular loss
• the caliceal mucosa is distended to one or two urothelial cells
• impaired bladder function and subsequent hydronephrosis are often associated with a reflux nephropathy
• renal parenchyma is thinned
• homozygotes display tubular atrophy
• the thickness of the urothelium varies with the degree of bladder distention, stretching to a thickness of two cells in the most distended area
• a significant number of older male homozygotes have massively swollen bladders
• homozygotes fail to urinate, leading to a massive expansion of the bladder

nervous system
• homozygotes display cerebellar damage, manifested as severe loss of Purkinje cells, intensive astrogliosis, and vacuolation of neurons in deep cerebellar nuclei
• older mice (>18 months) show intensive astrogliosis
• 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
• at 5-10 months, homozygotes exhibit axonal swelling in the gracile nucleus
• 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
• unlike AGU patients, where loss of Purkinje cells is scattered, homozygotes display widespread loss of Purkinje cells

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

Mouse Models of Human Disease
OMIM IDRef(s)
Aspartylglucosaminuria; AGU 208400 J:37022