Abstract: TH-PO556
Familial Hypocalciuric Hypercalcemia (FHH) Induced by Gene Deletion of Transient Receptor Potential Canonical 1 (TRPC1) Channels Is Independent of Gender, Like Ca Sensing Receptor (CaSR) Mutations
Session Information
- Bone and Mineral Metabolism: Basic
November 07, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Bone and Mineral Metabolism
- 401 Bone and Mineral Metabolism: Basic
Authors
- Khan, Usman A., University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, United States
- Eby, Bonnie, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, United States
- Lau, Alexander, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, United States
- Tariq, Ezza, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, United States
- Mahmood, Muhammad Bilal, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, United States
- Lau, Kai, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, United States
Background
Previously in TRPC1 null males, we reported the mouse phenotypes of FHH, causally related to reduced cell free [Ca] & hyperparathyroidism, like human FHH induced by haploid loss-of-function mutations in the CaSR gene. But haploid TRPC1 deletion induces only hypercalcemia, no hypocalciuria or hyperparathyroidism. Here we tested the hypothesis that phenotypes in TRPC1 null mutation are gender non-specific, like CaSR mutations.
Methods
In age-matched female mice, we performed classical metabolic balance studies & measured blood & urine Ca & Mg.by standard methods. We analyzed creatinine by HPLC & calciotropic hormones by mouse ELISA.
Results
Similar to null males, 7 mon old TRPC1 null females also exhibited hypocalciuria, whether expressed as mean 24 h urine Ca (1 ± 0.1 [SE] vs 1.6 ± 0.1 mg/d, p<0.03), as urine Ca:creat ratio (2 ± 0.2 vs 3 ± 0.1, p<0.02), or as Ca clearance (13 ± 2 vs 22 ± 1 μl/min, p< 0.01). Like null males, TRPC1 null females were also hypercalcemic, whether fasted (9.8 ± 0.3 vs 8.1 ± 0.4 mg%, p<0.005) or fed ad lib (9.6 ± 0.2 vs 8.5 ± 0.2 mg%, p<0.005). Mean fasting serum PTH in TRPC1 null females (609 vs.461 pg/ml) was numerically higher, but shy of statistical significance which we found in null males. But the hypercalcemia in null females failed to suppress PTH, suggesting similar dysregulation in PTH secretion by TRPC1 deficiency like the null males. Indeed, over the same range of serum Ca (9.6 - 10.8 m%), PTH was 35% higher in null females (652 ± 45 vs 484 ± 42 pg/ml, p<0.04). In contrast to the disturbed Ca homeostasis, there was no difference between null & wild type females in serum or urine Mg, again, similar to comparable data on Mg metabolism between null & wild type males. Mean fasting serum calcitriol (353 vs 332 pg/ml) & calcitonin (2.1 vs. 2.1 pg/ml) were similar between female genotypes, like comparable data between male genotypes.
Conclusion
We conclude that deletion of the gene encoding TRPC1 channels produces the phenotypes of hypocalciuric hypercalcemia in females as in males though hyperparathyroidism is milder. Our data support the current concept that alongside CaSR, by mediating store-operated Ca entry, TRPC1 plays a key role in intracellular Ca homeostasis & in regulating PTH secretion.
Funding
- NIDDK Support