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A novel mouse model for familial hypocalciuric hypercalcemia (FHH1) reveals PTH-dependent and independent CaSR defects


Küng, Catharina J; Daryadel, Arezoo; Fuente, Rocío; Haykir, Betül; de Angelis, Martin Hrabě; Hernando, Nati; Rubio-Aliaga, Isabel; Wagner, Carsten A (2024). A novel mouse model for familial hypocalciuric hypercalcemia (FHH1) reveals PTH-dependent and independent CaSR defects. Pflügers Archiv : European Journal of Physiology, 476(5):833-845.

Abstract

The Calcium-sensing receptor (CaSR) senses extracellular calcium, regulates parathyroid hormone (PTH) secretion, and has additional functions in various organs related to systemic and local calcium and mineral homeostasis. Familial hypocalciuric hypercalcemia type I (FHH1) is caused by heterozygous loss-of-function mutations in the CaSR gene, and is characterized by the combination of hypercalcemia, hypocalciuria, normal to elevated PTH, and facultatively hypermagnesemia and mild bone mineralization defects. To date, only heterozygous Casr null mice have been available as model for FHH1. Here we present a novel mouse FHH1 model identified in a large ENU-screen that carries an c.2579 T > A (p.Ile859Asn) variant in the Casr gene (Casr$^{BCH002}$ mice). In order to dissect direct effects of the genetic variant from PTH-dependent effects, we crossed Casr$^{BCH002}$ mice with PTH deficient mice. Heterozygous Casr$^{BCH002}$ mice were fertile, had normal growth and body weight, were hypercalcemic and hypermagnesemic with inappropriately normal PTH levels and urinary calcium excretion replicating some features of FHH1. Hypercalcemia and hypermagnesemia were independent from PTH and correlated with higher expression of claudin 16 and 19 in kidneys. Likewise, reduced expression of the renal TRPM6 channel in Casr$^{BCH002}$ mice was not dependent on PTH. In bone, mutations in Casr rescued the bone phenotype observed in Pth null mice by increasing osteoclast numbers and improving the columnar pattern of chondrocytes in the growth zone. In summary, Casr$^{BCH002}$ mice represent a new model to study FHH1 and our results indicate that only a part of the phenotype is driven by PTH.

Abstract

The Calcium-sensing receptor (CaSR) senses extracellular calcium, regulates parathyroid hormone (PTH) secretion, and has additional functions in various organs related to systemic and local calcium and mineral homeostasis. Familial hypocalciuric hypercalcemia type I (FHH1) is caused by heterozygous loss-of-function mutations in the CaSR gene, and is characterized by the combination of hypercalcemia, hypocalciuria, normal to elevated PTH, and facultatively hypermagnesemia and mild bone mineralization defects. To date, only heterozygous Casr null mice have been available as model for FHH1. Here we present a novel mouse FHH1 model identified in a large ENU-screen that carries an c.2579 T > A (p.Ile859Asn) variant in the Casr gene (Casr$^{BCH002}$ mice). In order to dissect direct effects of the genetic variant from PTH-dependent effects, we crossed Casr$^{BCH002}$ mice with PTH deficient mice. Heterozygous Casr$^{BCH002}$ mice were fertile, had normal growth and body weight, were hypercalcemic and hypermagnesemic with inappropriately normal PTH levels and urinary calcium excretion replicating some features of FHH1. Hypercalcemia and hypermagnesemia were independent from PTH and correlated with higher expression of claudin 16 and 19 in kidneys. Likewise, reduced expression of the renal TRPM6 channel in Casr$^{BCH002}$ mice was not dependent on PTH. In bone, mutations in Casr rescued the bone phenotype observed in Pth null mice by increasing osteoclast numbers and improving the columnar pattern of chondrocytes in the growth zone. In summary, Casr$^{BCH002}$ mice represent a new model to study FHH1 and our results indicate that only a part of the phenotype is driven by PTH.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology
Dewey Decimal Classification:610 Medicine & health
570 Life sciences; biology
Uncontrolled Keywords:Physiology (medical), Clinical Biochemistry, Physiology
Language:English
Date:1 May 2024
Deposited On:01 Mar 2024 13:12
Last Modified:30 Jun 2024 03:38
Publisher:Springer
ISSN:0031-6768
OA Status:Hybrid
Publisher DOI:https://doi.org/10.1007/s00424-024-02927-y
PubMed ID:38386045
Project Information:
  • : FunderSNSF
  • : Grant ID176125
  • : Project TitleMolecular mechanisms of mammalian phosphate sensing and homeostatic control
  • : FunderUniversity of Zurich
  • : Grant ID
  • : Project Title
  • Content: Published Version
  • Language: English
  • Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)