About   Help   FAQ
Phenotypes Associated with This Genotype
Genotype
MGI:3610388
Allelic
Composition
Hnf1atm1Mya/Hnf1atm1Mya
Genetic
Background
involves: 129S2/SvPas
Find Mice Using the International Mouse Strain Resource (IMSR)
Mouse lines carrying:
Hnf1atm1Mya mutation (0 available); any Hnf1a mutation (29 available)
phenotype observed in females
phenotype observed in males
N normal phenotype
mortality/aging
• 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
• at birth, homozygotes are obtained at a slightly reduced frequency (20% vs expected 25%), suggesting embryonic/perinatal loss

endocrine/exocrine glands
• not significant after adjustment for body weight
• notable, but not significant if adjusting for reduced body weight

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
• progressive severity with age
• 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
• 65% loss of arginine in the urine vs 0.4% in wild-type controls
• 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
• 65% loss of arginine in the urine vs 0.4% in wild-type controls
• 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/body
• after weaning, the body weight of mutant mice is 40%-80% that of wild-type littermates (J:31627)
• 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)
• 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

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
DO ID OMIM ID(s) Ref(s)
phenylketonuria DOID:9281 OMIM:261600
J:31627


Contributing Projects:
Mouse Genome Database (MGD), Gene Expression Database (GXD), Mouse Models of Human Cancer database (MMHCdb) (formerly Mouse Tumor Biology (MTB)), Gene Ontology (GO)
Citing These Resources
Funding Information
Warranty Disclaimer, Privacy Notice, Licensing, & Copyright
Send questions and comments to User Support.
last database update
03/19/2024
MGI 6.23
The Jackson Laboratory