Analysis Tools
mortality/aging
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• only 50% of homozygotes survive to P26, with viability sharply reduced at P25
• less than 15% of homozygotes survive to P42, and less than 1% survive beyond 3 months
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• at birth, homozygotes are obtained at a slightly reduced frequency (20% vs expected 25%), suggesting embryonic/perinatal loss
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endocrine/exocrine glands
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• not significant after adjustment for body weight
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• notable, but not significant if adjusting for reduced body weight
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liver/biliary system
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• at ~P14, homozygotes show severe hepatomegaly
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• at ~P14, the mutant liver to body weight ratio reaches 10%, and is on average twice that of heterozygous and wild-type littermates
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• 20% of homozygotes with enlarged livers display steatosis
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• homozygotes exhibit increased cholesterol, transaminase, and bilirubin levels, suggesting hepatocellular damage and liver dysfunction
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homeostasis/metabolism
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• weaned homozygotes exhibit very high hydroxyproline levels, and suffer from severe hyperphenylalaninemia (9- to 70-fold increase) caused by lack of transcription of the phenylalanine hydroxylase gene
• in contrast, levels of arginine, uric acid, and lysine are significantly reduced, while postprandial glycemia remains unaffected
• surprisingly, albumin and total plasma protein content is comparable to that of wild-type littermates
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• weaned homozygotes exhibit very high plasma hydroxyproline levels
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• homozygotes suffer from severe hyperphenylalaninemia (9- to 70-fold increase)
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• homozygotes exhibit a mild hyperammonemia (1.5- to 2-fold increase), that is often associated with orotic aciduria
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• homozygotes exhibit a mild (3- to 10-fold) increase in plasma bilirubin levels
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• progressive severity with age
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• homozygotes probably attempt to compensate for their massive urinary glucose loss with constitutively active gluconeogenesis and polyphagia
• defective glucose/energy balance eventually leads to protein catabolism and wasting
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• homozygotes exhibit increased renal leakage in the proximal tubule reabsorption process, with glucose leaking 878 times more than in wild-type littermates
• Scatchard plot analysis of phlorizin binding to brush border vesicles indicates a 2-fold reduction in the number Na+/glucose cotransporter molecules
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aminoaciduria
(
J:31627
)
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• homozygotes exhibit increased renal leakage in the proximal tubule reabsorption process, resulting in loss of arginine (65% loss vs 0.4% in wild-type) and other amino acids and metabolites (e.g. citrulline, hydroxyproline, uric acid) in the urine
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argininuria
(
J:31627
)
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• 65% loss of arginine in the urine vs 0.4% in wild-type controls
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• as early as P2-P5, normoglycemic homozygous pups exhibit very high urine glucose concentrations (240-1400 mM), with an average daily glucose loss of 600 mg
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• homozygotes exhibit an ~6-fold increase in urinary calcium/creatine ratio relative to wild-type mice
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• mild hyperammonemia is often associated with orotic aciduria
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renal/urinary system
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• homozygotes exhibit increased renal leakage in the proximal tubule reabsorption process, with glucose leaking 878 times more than in wild-type littermates
• Scatchard plot analysis of phlorizin binding to brush border vesicles indicates a 2-fold reduction in the number Na+/glucose cotransporter molecules
|
aminoaciduria
(
J:31627
)
|
• homozygotes exhibit increased renal leakage in the proximal tubule reabsorption process, resulting in loss of arginine (65% loss vs 0.4% in wild-type) and other amino acids and metabolites (e.g. citrulline, hydroxyproline, uric acid) in the urine
|
argininuria
(
J:31627
)
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• 65% loss of arginine in the urine vs 0.4% in wild-type controls
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• as early as P2-P5, normoglycemic homozygous pups exhibit very high urine glucose concentrations (240-1400 mM), with an average daily glucose loss of 600 mg
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• homozygotes exhibit an ~6-fold increase in urinary calcium/creatine ratio relative to wild-type mice
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• mild hyperammonemia is often associated with orotic aciduria
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• homozygotes show an ~3-fold reduction in the glomerular filtration rate, as calculated on the basis of renal creatinine clearance normalized per body weight
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• in homozygotes, diuresis is 2.6-15 times higher and in some cases reaches 85% of body weight in 24 hrs
• 50% of homozygotes show a daily diuresis of >40% of their body weight
• as expected, polyuria shows a positive and significant correlation with urinary glucose loss
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growth/size/body
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• after weaning, the body weight of mutant mice is 40%-80% that of wild-type littermates
(J:31627)
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• homozygotes start exhibiting progressive wasting and cachexia at the end of the second postnatal week
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• homozygotes exhibit growth retardation after the first postnatal week (P7)
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• at ~P14, homozygotes show severe hepatomegaly
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• at ~P14, the mutant liver to body weight ratio reaches 10%, and is on average twice that of heterozygous and wild-type littermates
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behavior/neurological
polyphagia
(
J:31627
)
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• the few surviving weaned homozygotes are polyphagic, with a 30% increase in food intake per body weight unit
• weaned homozygotes cannot tolerate overnight fasting, become weak and die the next morning
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muscle
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• by P20, homozygotes display muscular atrophy
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digestive/alimentary system
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• 20% of weaned homozygotes show a disorganized, looser gastric glandular epithelium of reduced thickness
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skeleton
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• by P20, homozygotes exhibit extensive bone demineralization
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adipose tissue
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• by P20, homozygotes show loss of subcutaneous fat
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integument
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• by P20, homozygotes show loss of subcutaneous fat
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cellular
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| phenylketonuria | DOID:9281 |
OMIM:261600 |
J:31627 | |
