Phenotypes associated with this allele

• Allele Symbol: Slc10a1^tm1Tac
• Allele Name: targeted mutation 1, Taconic
• Allele ID: MGI:6356556
• Summary: 1 genotype

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Slc10a1^tm1Tac/Slc10a1^tm1Tac	either: B6.Cg-Slc10a1^tm1Tac or (involves: 129S/SvEv * C57BL/6J)	MGI:6690421

Genotype
MGI:6690421

hm1

• Allelic Composition: Slc10a1^tm1Tac/Slc10a1^tm1Tac
• Genetic Background: either: B6.Cg-Slc10a1^tm1Tac or (involves: 129S/SvEv * C57BL/6J)

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

homeostasis/metabolism

homeostasis/metabolism phenotype ( J:274149 )

N • both hypercholanemic and normocholanemic mice show normal serum aspartate transaminase (AST) and alanine transaminase (ALT) levels relative to wild-type controls

increased circulating bilirubin level ( J:274149 )

• at 2 months of age, hypercholanemic (but not normocholanemic) mice show a moderate increase in serum conjugated bilirubin levels relative to wild-type controls

increased circulating alkaline phosphatase level ( J:274149 )

• at 2 months of age, hypercholanemic (but not normocholanemic) mice show a significant increase in serum ALP levels

abnormal bile salt homeostasis ( J:274149 )

• in sandwich cultures, primary mouse hepatocytes (PMHs) show absence of sodium-dependent taurocholic acid (TCA) uptake but normal TCA uptake under sodium-free conditions

• in the presence of Myrcludex B (a peptide inhibitor of hepatitis B virus entry), PMHs show a similar TCA uptake in sodium-dependent as well as sodium-free conditions, unlike wild-type PHMs where Myrcludex B abrogates sodium-dependent TCA uptake but has no effect on TCA uptake under sodium-free conditions

• after i.v. administration of TCA, normocholanemic mice show a significant delay in serum TCA elimination (t1/2 = 5.3 min vs 1.5 min in wild-type controls) as well as delayed biliary excretion of TCA

• after gallbladder cannulation (with no prior TCA administration), hypercholanemic mice show a marked delay in total serum BA clearance (t1/2 > 40 min)

• hypercholanemic (but not normocholanemic) mice show a significant decrease in total fecal BA excretion and very high urinary BA levels with no changes in biliary excretion of BAs relative to wild-type controls

increased bile salt level ( J:274149 )

• on a standard diet, 60%-75% of adult mice show normal total serum bile acid (BA) levels (normocholanemia), whereas the remaining subset show significantly increased total serum BA levels reaching millimolar concentrations (hypercholanemia)

• mice with high serum BA concentrations show significant increases in TCA, tauro-alpha-muricholic acid and tauro-beta-muricholic acids, and a relatively mild increase in deoxycholic acid (DCA)

• hypercholanemic mice show a shift toward increased conjugated BA species (87 +/- 12% of total versus 59.8 +/- 12% in wild-type controls) whereas normocholanemic mice do not exhibit this shift

• young normocholanemic mice fed with 0.1% ursodeoxycholicacid (UDCA) rapidly develop extremely high serum BA levels due to a significant increase in conjugated BAs, mainly TCA and tauro-beta-muricholic acid; unconjugated species tend to be increased in a subset of mice

• whereas 2 of 8 adult mice fed with UDCA cannot be forced into hypercholanemia, another 2 of 8 adult mice are already hypercholanemic pre-UDCA and remain extremely hypercholanemic post-UDCA

abnormal urine homeostasis ( J:274149 )

• hypercholanemic (but not normocholanemic) mice show a significant increase in urinary BA levels, mainly taurine-conjugated muricholates and cholate

decreased physiological sensitivity to xenobiotic ( J:274149 )

• primary mouse hepatocytes (PMHs) are insensitive to Myrcludex B (a synthetic preS1 lipopeptide derived from the hepatitis B virus (HBV) L-protein), unlike wild-type PMHs where sodium-dependent taurocholic acid (TCA) uptake is inhibited by Myrcludex B

abnormal xenobiotic pharmacokinetics ( J:274149 )

• following i.v. injection of radiolabeled Myrcludex B-derived lipopeptide, mice show virtually no accumulation of Myrcludex B signal in the liver, unlike wild-type controls; instead, non-liver-bound peptide accumulates in the kidneys, where it is eliminated from the circulation

growth/size/body

decreased body weight ( J:274149 )

• hypercholanemic (but not normocholanemic) mice exhibit a significantly reduced body weight postweaning and at 2 months of age

liver/biliary system

liver/biliary system phenotype ( J:274149 )

N • liver morphology and the ratios of liver weight to body weight are normal, and no signs of cholestasis, inflammation or hepatocellular damage are observed

abnormal bile secretion ( J:274149 )

• after gallbladder cannulation, hypercholanemic (but not normocholanemic) mice show a trend toward slightly reduced bile flow relative to wild-type controls

digestive/alimentary system

abnormal feces composition ( J:274149 )

• hypercholanemic (but not normocholanemic) mice show a significant decrease in total fecal BA excretion relative to wild-type controls

mortality/aging

increased susceptibility to induced morbidity/mortality ( J:274149 )

• hypercholanemic (but not normocholanemic) mice die shortly after i.v. injection of a single bolus of TCA (150 umol/kg body weight)

renal/urinary system

abnormal urine homeostasis ( J:274149 )

• hypercholanemic (but not normocholanemic) mice show a significant increase in urinary BA levels, mainly taurine-conjugated muricholates and cholate