Phenotypes associated with this allele

• Allele Symbol: Cyp27a1^tm1Elt
• Allele Name: targeted mutation 1, Eran Leitersdorf
• Allele ID: MGI:2181406
• Summary: 3 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Cyp27a1^tm1Elt/Cyp27a1^tm1Elt	B6.129-Cyp27a1^tm1Elt/J	MGI:5824134
hm2	Cyp27a1^tm1Elt/Cyp27a1^tm1Elt	involves: 129/Sv * C57BL/6J	MGI:3621428
cx3	Cyp27a1^tm1Elt/Cyp27a1^tm1Elt Cyp2r1^tm1(KOMP)Vlcg/Cyp2r1^tm1(KOMP)Vlcg	involves: C57BL/6J * C57BL/6N * C57BL/6NTac	MGI:5824136

Genotype
MGI:5824134

hm1

• Allelic Composition: Cyp27a1^tm1Elt/Cyp27a1^tm1Elt
• Genetic Background: B6.129-Cyp27a1^tm1Elt/J

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

homeostasis/metabolism

decreased circulating phosphate level ( J:223194 )

• serum phosphorus level is decreased slightly from 12.3 mg/dL at 3-5 weeks of age to 10.2 mg/dL on maturity and remains stable thereafter

abnormal vitamin D level ( J:223194 )

• mice show a 2- to 3-fold increase in serum 25(OH)D3 level at 6-14 weeks of age, as determined by RIA analysis

• at 10 weeks of age, HPLC analysis revealed that serum 25(OH)D3 values are 52.2 ng/mL versus 19.4 ng/mL in wild-type controls

• in contrast, serum 1,25(OH)2D3 level is comparable to that in wild-type controls (51-68 pg/mL) at 5-16 weeks of age

liver/biliary system

enlarged liver ( J:223194 )

• livers are enlarged by ~45%

growth/size/body

enlarged liver ( J:223194 )

• livers are enlarged by ~45%

Genotype
MGI:3621428

hm2

• Allelic Composition: Cyp27a1^tm1Elt/Cyp27a1^tm1Elt
• Genetic Background: involves: 129/Sv * C57BL/6J

homeostasis/metabolism

homeostasis/metabolism phenotype ( J:115373 )

♂N • males show normal plasma levels of glucose, corticosterone, ACTH, and testosterone at 3-4 months of age

decreased intestinal cholesterol absorption ( J:115373 )

♂ • severe reduction in intestinal cholesterol absorption (4% from 54% in wild-type controls)

♂ • intestinal cholesterol absorption is restored to normal levels by cholic acid feeding

abnormal circulating cholesterol level ( J:48127 )

• concentration of circulating 7-alpha hydroxycholesterol is 4-10 fold higher in null mice

increased circulating triglyceride level ( J:115373 )

♂ • 2-fold increase in plasma total triacylglycerol levels on a conventional low fat, low cholesterol diet

♂ • plasma triacylglycerol levels are essentially normalized by cholic acid feeding

increased circulating VLDL triglyceride level ( J:115373 )

♂ • marked increase in plasma triacylglycerol levels is confined to the VLDL fraction

abnormal bile salt homeostasis ( J:115373 )

♂ • 5-fold increase in cholesterol 7alpha-hydroxylase activity relative to wild-type controls

decreased bile salt level ( J:115373 )

♂ • bile acid pool size is only 27% of that in wild-type controls

♂ • total bile acid synthesis is about 47% of that in wild-type controls, as measured by the rate of fecal bile acid excretion

decreased cholesterol level ( J:115373 )

♂ • slight reduction of cholesterol concentration in the lungs

increased fatty acids level ( J:115373 )

♂ • 70% increase in hepatic fatty acid synthesis relative to wild-type controls

♂ • marked shift in hepatic fatty acid composition with a ~70% increase in the proportion of oleic (18:1) to stearic acid (18:0)

♂ • hepatic fatty acid synthesis is essentially normalized by cholic acid feeding

♂ • no change in the rates of fatty acid synthesis in adrenal gland, lung, or small intestine tissue

abnormal vitamin D level ( J:48127 )

• levels of 25-hydroxyvitamin D are slightly higher in nulls than in wild-type

increased sterol level ( J:115373 )

♂ • significant increase of two non-cholesterol sterols, identified as the two forms of lathosterol, in the adrenal glands, not detected in wild-type adrenals

♂ • trace amounts of the two lathosterol forms (~4% of total tissue sterol content) in the lungs, unlike in wild-type controls

increased cholesterol level ( J:48127 , J:115373 )

• amount of 7 alpha-hydroxycholesterol in liver, kidney and brain is markedly higher in null animals (J:48127)

♂ • 48% increase of cholesterol concentration in the adrenal glands relative to wild-type controls (J:115373)

♂ • marked increase in cholesterol synthesis in the liver and adrenal gland (4-fold), lung (2.9-fold), spleen (2.4-fold), and small intestine (1.8-fold) (J:115373)

♂ • 2.5-fold increase in whole animal cholesterol synthesis relative to wild-type controls, with ~90% attributed to hepatic synthesis (J:115373)

♂ • cholic acid feeding reduces sterol synthesis in the liver and adrenal gland to values significantly below those seen in wild-type mice fed the basal diet alone (J:115373)

increased circulating cholesterol level ( J:115373 )

♂ • 30% increase in plasma total cholesterols level on a conventional low fat, low cholesterol diet

increased circulating VLDL cholesterol level ( J:115373 )

♂ • marked increase in plasma cholesterol levels is confined to the VLDL fraction

increased liver triglyceride level ( J:115373 )

♂ • 2.4-fold increase in hepatic triacylglycerol levels relative to wild-type controls

♂ • hepatic triacylglycerol levels are essentially normalized by cholic acid feeding

liver/biliary system

enlarged liver ( J:115373 )

♂ • significant hepatomegaly at 3-4 months of age

♂ • hepatomegaly is almost fully reversed by cholic acid or chenodeoxycholic acid feeding

increased liver weight ( J:115373 )

♂ • 40% increase in liver weight relative to wild-type controls

increased liver triglyceride level ( J:115373 )

♂ • 2.4-fold increase in hepatic triacylglycerol levels relative to wild-type controls

♂ • hepatic triacylglycerol levels are essentially normalized by cholic acid feeding

abnormal bile composition ( J:48127 , J:115373 )

• concentration of bile acids in hydrolyzed bile sample from knockout mice is 0.9 mg/ml compared to about 8 mg/ml in a wild-type sample (J:48127)

♂ • molar ratio of cholesterol in gallbladder bile is double that in wild-type controls, due to a significant reduction in bile acid and phospholipid levels while biliary cholesterol concentration remains normal (J:115373)

♂ • bile acid concentration in gallbladder bile is only 37% of that in wild-type controls (J:115373)

♂ • however, bile acid species are similar to those in wild-type controls, with cholic acid predominating in both cases (J:115373)

endocrine/exocrine glands

enlarged adrenocortical cells ( J:115373 )

♂ • upon histology, adrenomegaly reflects cortical cell hypertrophy

increased adrenal gland weight ( J:115373 )

♂ • 45% increase in adrenal gland weight relative to wild-type controls

enlarged adrenal glands ( J:115373 )

♂ • significantly enlarged adrenal glands at 3-4 months of age

♂ • adrenomegaly is NOT reversed by cholic acid feeding

digestive/alimentary system

decreased intestinal cholesterol absorption ( J:115373 )

♂ • severe reduction in intestinal cholesterol absorption (4% from 54% in wild-type controls)

♂ • intestinal cholesterol absorption is restored to normal levels by cholic acid feeding

abnormal feces composition ( J:115373 )

♂ • fecal bile acid excretion is about 47% of that in wild-type controls

♂ • 2.5-fold increase in fecal neutral sterol excretion relative to wild-type controls

renal/urinary system

decreased kidney weight ( J:115373 )

♂ • significant reduction in kidney weight at 3-4 months of age

nervous system

decreased brain weight ( J:115373 )

♂ • significant reduction in brain weight at 3-4 months of age

growth/size/body

enlarged liver ( J:115373 )

♂ • significant hepatomegaly at 3-4 months of age

♂ • hepatomegaly is almost fully reversed by cholic acid or chenodeoxycholic acid feeding

increased liver weight ( J:115373 )

♂ • 40% increase in liver weight relative to wild-type controls

Genotype
MGI:5824136

cx3

• Allelic Composition: Cyp27a1^tm1Elt/Cyp27a1^tm1Elt; Cyp2r1^{tm1(KOMP)Vlcg}/Cyp2r1^{tm1(KOMP)Vlcg}
• Genetic Background: involves: C57BL/6J * C57BL/6N * C57BL/6NTac

homeostasis/metabolism

decreased circulating phosphate level ( J:223194 )

• serum phosphorus level is decreased slightly from 12.3 mg/dL at 3-5 weeks of age to 10.2 mg/dL on maturity and remains stable thereafter

abnormal vitamin D level ( J:223194 )

• serum 25(OH)D3 level is reduced by more than 50% at 6-14 weeks of age, similar to single Cyp2r1^{tm1(KOMP)Vlcg} homozygotes

• at 10 weeks of age, HPLC analysis revealed that serum 25(OH)D3 values are 5.9 ng/mL versus 5.2 ng/mL in single Cyp2r1^{tm1(KOMP)Vlcg} homozygotes and 19.4 ng/mL in wild-type controls

• in contrast, serum 1,25(OH)2D3 level is comparable to that in wild-type controls (51-68 pg/mL) at 5-16 weeks of age

liver/biliary system

enlarged liver ( J:223194 )

• livers are enlarged by ~35%

skeleton

skeleton phenotype ( J:223194 )

N • mice do not develop rickets and show normal serum calcium levels and tibial epiphyseal plates in response to a rachitogenic high-calcium and low-phosphorus diet, consistent with a normal serum concentration of 1,25(OH)2D3

growth/size/body

enlarged liver ( J:223194 )

• livers are enlarged by ~35%