Phenotypes Associated with This Genotype

Genotype
MGI:8265029

• Allelic Composition: Cacna1c^em1Gsp/Cacna1c⁺
• Genetic Background: C57BL/6J-Cacna1c^em1Gsp

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

mortality/aging

increased susceptibility to induced morbidity/mortality ( J:361120 )

♂ • 8-10-week-old mice are sensitive not only to the standard prolonged 16 hour fast before a GTT, but young mice are unable to survive other standard metabolic challenges, such as an insulin tolerance test

♂ • even with half the standard insulin administration for an insulin tolerance test (ITT), 8-10-week-old mice die within 45 min or insulin administration, while 14-20-week-old mice survive the ITT with a reduced insulin administration protocol

prenatal lethality, incomplete penetrance ( J:361120 )

• fewer than the expected number of heterozygotes are obtained

adipose tissue

abnormal adipose tissue amount ( J:361120 )

♂ • the major adipose depots (visceral and subcutaneous) are reduced

decreased subcutaneous adipose tissue amount ( J:361120 )

♂

behavior/neurological

polydipsia ( J:361120 )

♂ • mice drink more water

decreased food intake ( J:361120 )

♂ • males eat less than wild-type males in a metabolic cage experiment

homeostasis/metabolism

decreased glucagon secretion ( J:361120 )

♂ • low glucose elicits 56% lower glucagon secretion in isolated islets compared to wild-type islets

acidemia ( J:361120 )

♂ • mice show reduced serum bicarbonate indicating acidemia

decreased circulating bicarbonate level ( J:361120 )

♂ • mice show reduced serum bicarbonate indicating acidemia

hypoglycemia ( J:361120 )

♂ • mice at 8-10 weeks of age show a reduced trend towards reduced blood glucose in the fed state and by 2 hours of fasting, blood glucose in lower and remains lower for the entire testing period, indicating hypoglycemia

♂ • however, gluconeogenesis in a pyruvate tolerance test in both the fed and fasting state is similar to that in wild-type mice, inducing an elevation in blood glucose in both states

increased circulating adrenaline level ( J:361120 )

♂ • mice show a greater increase in serum epinephrine at baseline and in response to hypoglycemia induced by insulin compared to the increase seen in wild-type mice

♂ • however, mice show a similar increase in serum corticosterone levels in response to hypoglycemia induced by insulin as wild-type mice, suggesting that counterregulatory hormone responses remain intact

decreased circulating glucagon level ( J:361120 )

♂ • both baseline glucagon and the glucagon response to insulin-induced hypoglycemia appears blunted

decreased circulating insulin level ( J:361120 )

♂ • insulin levels are lower in both the fasted state and 30 min after a glucose bolus; while both wild-type and mutant mice show an increase in serum insulin after glucose administration, the response is blunted rather than exaggerated in mutants

♂ • however, glucose stimulated insulin secretion from isolated pancreatic islets is similar to wild-type islets

decreased circulating leptin level ( J:361120 )

♂ • serum leptin levels are diminished

increased circulating ketone body level ( J:361120 )

♂ • mice show elevated blood ketones in the fasted state

improved glucose tolerance ( J:361120 )

♂ • in the glucose tolerance test (GTT), mice at 10-14 weeks of age show normal baseline blood glucose before the bolus but show reduced excursion compared to wild-type mice

increased urine glucose level ( J:361120 )

♂ • mice show marked glycosuria despite normal renal function

increased insulin sensitivity ( J:361120 )

♂ • in an insulin tolerance test, mice fasted for 2 hours show the expected initial drop in blood glucose followed by the subsequent initiation of recovery towards normoglycemia, but blood glucose continues to decrease, despite lowering insulin to 1 unit/kg, suggesting enhanced insulin sensitivity and/or deficient counterregulatory response to hypoglycemia

cardiovascular system

prolonged QT interval ( J:361120 )

♂ • baseline rate-corrected QT interval (QTc) is prolonged

♂ • injection of the non-selective beta-adrenergic agonist isoproterenol prolongs QTc which remains prolonged 7 min later

growth/size/body

decreased body size ( J:361120 )

♂ • mice are smaller at weaning and remain smaller into adulthood

decreased body weight ( J:361120 )

• weights of males and females are lower at 10-12 weeks of age

integument

decreased subcutaneous adipose tissue amount ( J:361120 )

♂

renal/urinary system

increased urine glucose level ( J:361120 )

♂ • mice show marked glycosuria despite normal renal function

nervous system

abnormal channel response ( J:361120 )

♂ • hippocampal neurons from P2 pups show slower voltage-dependent inactivation than wild-type neurons when using Ba²⁺ as a charge carrier

♂ • calcium channel currents from smooth muscle cells isolated from the colon show a reduction in voltage-dependent inactivation when using Ba²⁺ as a charge carrier

♂ • however, isolated pancreatic beta cells show normal non-inactivating calcium channel currents and normal kinetics of voltage-gated calcium channel inactivation

endocrine/exocrine glands

endocrine/exocrine gland phenotype ( J:361120 )

♂N • no histological differences are seen in the adrenal medulla

decreased pancreatic alpha cell mass ( J:361120 )

♂

decreased glucagon secretion ( J:361120 )

♂ • low glucose elicits 56% lower glucagon secretion in isolated islets compared to wild-type islets

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Timothy syndrome		DOID:0060173	OMIM:601005	J:361120