Phenotypes associated with this allele

• Allele Symbol: Atp8b1^tm1Nbf
• Allele Name: targeted mutation 1, Nelson B Freimer
• Allele ID: MGI:3043815
• Summary: 3 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Atp8b1^tm1Nbf/Atp8b1^tm1Nbf	involves: 129S1/SvImJ * 129S4/SvJae	MGI:3043817
hm2	Atp8b1^tm1Nbf/Atp8b1^tm1Nbf	involves: 129S4/SvJae	MGI:3850427
cn3	Atp8b1^tm1Nbf/Atp8b1^tm1Nbf Por^tm1Wolf/Por^tm1Wolf Speer6-ps1^Tg(Alb-cre)21Mgn/Speer6-ps1^+	involves: 129P2/OlaHsd * 129S4/SvJae * C57BL/6 * DBA	MGI:5618808

Genotype
MGI:3043817

hm1

• Allelic Composition: Atp8b1^tm1Nbf/Atp8b1^tm1Nbf
• Genetic Background: involves: 129S1/SvImJ * 129S4/SvJae

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

growth/size/body

increased susceptibility to weight loss ( J:89817 )

• on a bile salt supplemented diet homozygous mutants lose weight

postnatal growth retardation ( J:89817 )

• prior to weaning homozygous pups are growth impaired, however this size difference resolved with age

enlarged liver ( J:89817 )

• the liver is slightly enlarged in homozygous mutants

• on a bile salt supplemented diet homozygous mutants develop significantly enlarged livers with increased hepatocyte proliferation

homeostasis/metabolism

increased circulating bilirubin level ( J:89817 )

• on a bile salt supplemented diet serum bilirubin levels are elevated in homozygous mutants compared to wild-type mice

• on a normal diet serum bilirubin levels are normal in homozygous mutants

increased circulating aspartate transaminase level ( J:89817 )

• serum aspartate transaminase is mildly elevated

abnormal bile salt level ( J:89817 )

• serum bile salt levels are elevated

• on a bile salt supplemented diet homozygous mutants do not increase the rate of bile salt turnover and therefore develop much higher bile salt levels compared to wild-type mice

liver/biliary system

enlarged liver ( J:89817 )

• the liver is slightly enlarged in homozygous mutants

• on a bile salt supplemented diet homozygous mutants develop significantly enlarged livers with increased hepatocyte proliferation

abnormal bile secretion ( J:89817 )

• enhanced bile flow and output of the principal bile components

abnormal liver physiology ( J:89817 )

• on a normal diet homozygotes do dot develop jaundice or diarrhea and most liver enzyme activities are normal

• on a bile salt supplemented diet liver enzyme activities in homozygous mutants increase

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
NOT	intrahepatic cholestasis	DOID:1852		J:89817

Genotype
MGI:3850427

hm2

• Allelic Composition: Atp8b1^tm1Nbf/Atp8b1^tm1Nbf
• Genetic Background: involves: 129S4/SvJae

hearing/vestibular/ear

abnormal cochlea morphology ( J:150079 )

abnormal outer hair cell stereociliary bundle morphology ( J:150079 )

• by P16 loss of stereocilia is seen in some mice

• however, on P4 stereocilia appear normal indicating normal development

cochlear inner hair cell degeneration ( J:150079 )

• beginning by 1 month of age

cochlear outer hair cell degeneration ( J:150079 )

• beginning by P16

• at P16 degeneration is more prominent in the basal turn of the cochlea

• at 1 month of age, clear loss of outer hair cells and degeneration of the surrounding supporting cells is seen

degeneration of organ of Corti supporting cells ( J:150079 )

• at 1 month of age, degeneration of the supporting cells is seen secondary to loss of outer hair cells

organ of Corti degeneration ( J:150079 )

• complete degeneration of the organ of Corti is seen at 6 months of age

increased or absent threshold for auditory brainstem response ( J:150079 )

• significant threshold shifts at all frequencies in 1, 3, and 6 month old mice but not in 16 day old mice

• however, interwave intervals are not significantly different from controls in mutants at 1 and 6 months of age indicating hearing loss is not retrocochlear in origin

nervous system

abnormal outer hair cell stereociliary bundle morphology ( J:150079 )

• by P16 loss of stereocilia is seen in some mice

• however, on P4 stereocilia appear normal indicating normal development

cochlear inner hair cell degeneration ( J:150079 )

• beginning by 1 month of age

cochlear outer hair cell degeneration ( J:150079 )

• beginning by P16

• at P16 degeneration is more prominent in the basal turn of the cochlea

• at 1 month of age, clear loss of outer hair cells and degeneration of the surrounding supporting cells is seen

abnormal cochlear ganglion morphology ( J:150079 )

• decreased number of spiral ganglion cells and nerve fibers in all turns in mice at 1 month of age

Genotype
MGI:5618808

cn3

• Allelic Composition: Atp8b1^tm1Nbf/Atp8b1^tm1Nbf; Por^tm1Wolf/Por^tm1Wolf; Speer6-ps1^{Tg(Alb-cre)21Mgn}/Speer6-ps1⁺
• Genetic Background: involves: 129P2/OlaHsd * 129S4/SvJae * C57BL/6 * DBA

mortality/aging

increased susceptibility to induced morbidity/mortality ( J:215915 )

• mice fed a 0.03% cholic acid-supplemented diet directly from weaning die within a week after the start of the diet

• however, mice fed a 0.03% cholic acid-supplemented diet starting at 4 weeks of age for 4 weeks survive

growth/size/body

weight loss ( J:215915 )

• mice fail to gain weight and even lose weight after starting of 0.03% cholic acid-supplemented diet at 4 weeks of age

increased liver weight ( J:215915 )

• liver weights are increased in mice fed a cholic acid-supplemented diet for 4 weeks starting at 4 weeks of age

• mice fed a cholic acid-supplemented diet for 4 weeks starting at 4 weeks of age do not exhibit fibrosis in the liver

homeostasis/metabolism

increased circulating bilirubin level ( J:215915 )

• after 4 weeks of cholic acid-supplemented diet started at 4 weeks of age, mice exhibit enhanced plasma bilirubin levels

increased circulating alanine transaminase level ( J:215915 )

• after 4 weeks of cholic acid-supplemented diet started at 4 weeks of age, mice exhibit a mild elevation in plasma alanine transaminase levels

increased circulating alkaline phosphatase level ( J:215915 )

• after 4 weeks of cholic acid-supplemented diet started at 4 weeks of age, mice exhibit a mild elevation in plasma alkaline phosphatase levels

abnormal bile salt homeostasis ( J:215915 )

• after 4 weeks on a cholic acid-supplemented diet, plasma bile salts predominantly consist of about 90% taurocholate (TC) and about 7% tauro-beta-muricholate (TbetaMC) and a low concentration of about 0.4% of the secondary bile salt taurochenodeoxycholate (TDC) is seen compared to about 70% TC and 20% TbetaMC in single Atp8b1 homozygotes

• after 4 weeks on a cholic acid-supplemented diet, biliary bile salts predominantly consist of about 90% TC and about 9% TbetaMC compared to 55% TC and 40% TbetaMC in single Atp8b1 homozygotes

• after 4 weeks on a cholic acid-supplemented diet, bile salt hydrophobicity index of plasma is elevated but the hydrophobicity index of bile is unaltered, indicating that the plasma bile salt pool is more hydrophobic

increased bile salt level ( J:215915 )

• after 4 weeks of cholic acid-supplemented diet started at 4 weeks of age, mice exhibit a strong elevation in plasma bile salt levels

liver/biliary system

bile duct proliferation ( J:215915 )

• mice fed a cholic acid-supplemented diet for 4 weeks starting at 4 weeks of age, exhibit a slight increase in bile duct proliferation

increased liver weight ( J:215915 )

• liver weights are increased in mice fed a cholic acid-supplemented diet for 4 weeks starting at 4 weeks of age

• mice fed a cholic acid-supplemented diet for 4 weeks starting at 4 weeks of age do not exhibit fibrosis in the liver

abnormal bile secretion ( J:215915 )

• after 4 weeks of cholic acid-supplemented diet started at 4 weeks of age, bile flow is strongly (about 3-fold) reduced

• mice, however show normal bile salt output when fed a cholic acid-supplemented diet for 4 weeks starting at 4 weeks of age

cholestasis ( J:215915 )

• mice fed a cholic acid-supplemented diet for 4 weeks starting at 4 weeks of age develop a severe cholestatic phenotype with mild liver damage

endocrine/exocrine glands

bile duct proliferation ( J:215915 )

• mice fed a cholic acid-supplemented diet for 4 weeks starting at 4 weeks of age, exhibit a slight increase in bile duct proliferation

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
intrahepatic cholestasis		DOID:1852		J:215915