möglich sobald bei der ZB eingereicht worden ist.
A novel mouse model for familial hypocalciuric hypercalcemia (FHH1) reveals PTH-dependent and independent CaSR defects.
Pflugers Arch. 476, 833-845 (2024)
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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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Schlagwörter
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
Zeitschrift
Pflügers Archiv
Quellenangaben
Band: 476,
Heft: 5,
Seiten: 833-845
Verlag
Springer
Verlagsort
Tiergartenstrasse 17, D-69121 Heidelberg, Germany
Nichtpatentliteratur
Publikationen
Begutachtungsstatus
Peer reviewed
Institut(e)
Institute of Experimental Genetics (IEG)
Förderungen
Helmholtz Zentrum in Munich
INFRAFRONTIER
INFRAFRONTIER