Mouse Genome Informatics
hm
    Hnf1atm1Mya/Hnf1atm1Mya
involves: 129S2/SvPas
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
       
mortality/aging
N
• at birth, homozygotes are obtained at a slightly reduced frequency (20% vs expected 25%), suggesting embryonic/perinatal loss (J:31627)
• 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

liver/biliary system
• at ~P14, homozygotes show severe hepatomegaly
• at ~P14, the mutant liver to body weight ratio reaches 10%, and is on average twice that of heterozygous and wild-type littermates
• 20% of homozygotes with enlarged livers display steatosis
• homozygotes exhibit increased cholesterol, transaminase, and bilirubin levels, suggesting hepatocellular damage and liver dysfunction
• newborn homozygotes appear slightly yellowish relative to wild-type pups

homeostasis/metabolism
• 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
• homozygotes exhibit a mild hyperammonemia (1.5- to 2-fold increase), that is often associated with orotic aciduria
• homozygotes exhibit a mild (3- to 10-fold) increase in plasma bilirubin levels
• 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
• 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
• 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
• 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
• homozygotes exhibit an ~6-fold increase in urinary calcium/creatine ratio relative to wild-type mice
• mild hyperammonemia is often associated with orotic aciduria

renal/urinary system
• 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
• 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
• 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
• homozygotes exhibit an ~6-fold increase in urinary calcium/creatine ratio relative to wild-type mice
• mild hyperammonemia is often associated with orotic aciduria
• homozygotes show an ~3-fold reduction in the glomerular filtration rate, as calculated on the basis of renal creatinine clearance normalized per body weight
• 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

growth/size
• after weaning, the body weight of mutant mice is 40%-80% that of wild-type littermates
• homozygotes start exhibiting progressive wasting and cachexia at the end of the second postnatal week
• homozygotes exhibit growth retardation after the first postnatal week (P7)

behavior/neurological
• 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

muscle
• by P20, homozygotes display muscular atrophy

digestive/alimentary system
• 20% of weaned homozygotes show a disorganized, looser gastric glandular epithelium of reduced thickness

skeleton
• by P20, homozygotes exhibit extensive bone demineralization

adipose tissue
• by P20, homozygotes show loss of subcutaneous fat

integument
• by P20, homozygotes show loss of subcutaneous fat

cellular

Mouse Models of Human Disease
OMIM IDRef(s)
Phenylketonuria; PKU 261600 J:31627