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Küng, C.J.* ; Daryadel, A.* ; Fuente, R.* ; Haykir, B.* ; Hrabě de Angelis, M. ; Hernando, N.* ; Rubio-Aliaga, I.* ; Wagner, C.A.*

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

Pflugers Arch. 476, 833-845 (2024)
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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 (CasrBCH002 mice). In order to dissect direct effects of the genetic variant from PTH-dependent effects, we crossed CasrBCH002 mice with PTH deficient mice. Heterozygous CasrBCH002 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 CasrBCH002 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, CasrBCH002 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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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Bone ; Calcium-sensing Receptor ; Fibroblast Growth Factor 23 ; Kidney ; Mouse Model ; Parathyroid Hormone; Calcium-sensing Receptor; Parathyroid-hormone; Rat-kidney; Expression; Localization; Transport; Nhe3
ISSN (print) / ISBN 0031-6768
e-ISSN 1432-2013
Journal Pflügers Archiv
Quellenangaben Volume: 476, Issue: 5, Pages: 833-845 Article Number: , Supplement: ,
Publisher Springer
Publishing Place Tiergartenstrasse 17, D-69121 Heidelberg, Germany
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Experimental Genetics (IEG)
Grants Helmholtz Zentrum in Munich
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