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Cecilia M Giachelli - One of the best experts on this subject based on the ideXlab platform.
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role of carbonic anhydrase ii in Ectopic Calcification
Cardiovascular Pathology, 2009Co-Authors: Rupak M Rajachar, Elyse Tung, Anh Q Truong, Amy Look, Cecilia M GiachelliAbstract:Abstract Introduction Osteopontin (OPN) is a potent inhibitor of Ectopic Calcification. Previous studies suggested that, in addition to blocking apatite crystal growth, OPN promoted regression of Ectopic Calcification by inducing the expression of acid-generating carbonic anhydrase II (CAR2) in monocyte-derived cells. Methods To test this hypothesis, OPN and CAR2 expression and Calcification of subcutaneously implanted glutaraldehyde-fixed bovine pericardium (GFBP) were studied in CAR2 mutant mice. Results Consistent with previous studies in Black Swiss mice, GFBP calcified to a greater extent in OPN-deficient mice compared to wild types on the C57Bl/6 background. GFBP implanted in CAR2-deficient mice (CAR2 −/− ) were significantly more calcified than those implanted into wild-type mice (CAR2 +/+ ) [37±5 vs. 20±6.5 μg Ca/mg tissue, respectively, at 30 days ( P 42 ±5 versus 20 ±4 μg Ca/mg tissue at 60 days, respectively ( P +/+ and CAR2 −/− mice, suggesting that OPN expression in the absence of CAR2 was not sufficient to mitigate Ectopic Calcification. Conclusions These results indicate that CAR2 expression is an important regulator of Ectopic Calcification, potentially by facilitating OPN mediated mineral regression.
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Mitigation of Ectopic Calcification in Osteopontin-Deficient Mice by Exogenous Osteopontin
Calcified Tissue International, 2005Co-Authors: Rachit Ohri, Elyse Tung, Rupak Rajachar, Cecilia M GiachelliAbstract:Ectopic Calcification is a major cause of bioprosthetic heart valve failure. New therapeutic opportunities are offered by the growing understanding that Ectopic Calcification is an actively regulated process involving several key gene products. One of these products, osteopontin (OPN), is a glycosylated phosphoprotein previously shown to inhibit apatite crystal formation, induce carbonic anhydrase II, and promote mineral resorption. In this study, OPN-deficient mice (OPN−/−) were utilized as an in vivo model to stimulate the Ectopic Calcification of glutaraldehyde-fixed bovine pericardium (GFBP) tissue and to examine OPN delivery and structure-function relationships with respect to its anti-calcific activity. Significant Calcification of GFBP tissue was obtained within 7 days of subcutaneous implantation in OPN−/− mice. Direct rescue of the Calcification phenotype was achieved by the administration of exogenous recombinant rat, histidine-fused OPN (rat His-OPN) to the implant site via soluble injection (up to 72% mitigation achieved) or adsorption onto the implant materials (up to 91% mitigation achieved). Effects were specific, since neither fibronectin nor polyhistidine alone could mitigate Calcification of GFBP. The maximum anti-calcific effect was achieved only when rat His-OPN was adequately phosphorylated and contained a functional arginine-glycine-aspartate (RGD) cell adhesive domain. Furthermore, CAII levels in host cells surrounding GFBP were greatest when phosphorylated, RGD-containing rat His-OPN was adsorbed. These data suggest that both physical inhibition, mediated by phosphorylation sites in OPN, as well as the induction of CAII and mineral regression, mediated by the RGD domain, contribute to the unique ability of OPN to mitigate Ectopic Calcification of bioprosthetic valve tissue.
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osteopontin inhibits mineral deposition and promotes regression of Ectopic Calcification
American Journal of Pathology, 2002Co-Authors: Susan Steitz, Mei Y Speer, Marc D Mckee, Lucy Liaw, Manuela Almeida, Hsueh Yang, Cecilia M GiachelliAbstract:Ectopic Calcification, the abnormal Calcification of soft tissues, can have severe clinical consequences especially when localized to vital organs such as heart valves, arteries, and kidneys. Recent observations suggest that Ectopic Calcification, like bone biomineralization, is an actively regulated process. These observations have led a search for molecular determinants of Ectopic Calcification. A candidate molecule is osteopontin (OPN), a secreted phosphoprotein invariantly associated with both normal and pathological mineral deposits. In the present study, OPN was found to be a natural inhibitor of Ectopic Calcification in vivo. Glutaraldehyde-fixed aortic valve leaflets showed accelerated and fourfold to fivefold greater Calcification after subcutaneous implantation into OPN-null mice compared to wild-type mice. In vitro and in vivo studies suggest that OPN not only inhibits mineral deposition but also actively promotes its dissolution by physically blocking hydroxyapatite crystal growth and inducing expression of carbonic anhydrase II in monocytic cells and promoting acidification of the extracellular milieu. These findings suggest a novel mechanism of OPN action and potential therapeutic approach to the treatment of Ectopic Calcification.
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Ectopic Calcification gathering hard facts about soft tissue mineralization
American Journal of Pathology, 1999Co-Authors: Cecilia M GiachelliAbstract:Ectopic Calcification is defined as inappropriate biomineralization occurring in soft tissues. 1 Ectopic Calcifications are typically composed of calcium phosphate salts, including hydroxyapatite, but can also consist of calcium oxalates and octacalcium phosphate as seen in kidney stones. 2 In uremic patients, a systemic mineral imbalance is associated with widespread Ectopic Calcification, referred to as metastatic Calcification. 3 In the absence of a systemic mineral imbalance, Ectopic Calcification is typically termed dystrophic Calcification. Often, these sites show evidence of tissue alteration and/or necrosis. Dystrophic mineralization is commonly observed in soft tissues as a result of injury, disease, and aging. Although most soft tissues can undergo Calcification, skin, kidney, tendons, and cardiovascular tissues appear particularly prone to developing this pathology. 4 In addition, a number of prosthetic devices are prone to Ectopic Calcification, as discussed below. Recent insights into the mechanisms regulating Ectopic Calcification have come from studies of cardiovascular Calcification, including that by Kim et al 5 in this issue of the Journal, and thus will be the major focus of this article. The reader is referred to other reviews for information about additional tissue-specific Ectopic Calcifications. 2,6,7
Daewon Jeong - One of the best experts on this subject based on the ideXlab platform.
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α lipoic acid attenuates coxsackievirus b3 induced Ectopic Calcification in heart pancreas and lung
Biochemical and Biophysical Research Communications, 2013Co-Authors: Hyo Shin Kim, Hongin Shin, Hyunsook Lim, Tae Yoon Lee, Kyung Hee Lee, Daewon JeongAbstract:Ectopic mineralization of soft tissues is known to be a typical response to systemic imbalance of various metabolic factors as well as tissue injury, leading to severe clinical consequences. In this study, coxsackievirus B3 (CVB3) infection in mice resulted in significant tissue injury, especially in the heart and pancreas. Inflammatory damage and apoptotic cell death were observed in CVB3-infected heart and pancreas tissues. Along with tissue damage, substantial Ectopic Calcification was detected in CVB3-infected heart, pancreas, and lung tissues, as determined by von Kossa staining and calcium content quantification. In addition, CVB3 infection induced upregulation of osteogenic signals, including six genes (BMP2, SPARC, Runx2, osteopontin, collagen type I, and osterix) in the heart, three genes (SPARC, osteopontin, and collagen type I) in the pancreas, and two genes (BMP2 and alkaline phosphatase) in the lung, as determined by quantitative real-time PCR analysis. Intriguingly, we showed that α-lipoic acid diminished CVB3-mediated inflammatory and apoptotic tissue damage, subsequently ameliorating Ectopic Calcification via the suppression of osteogenic signals. Collectively, our data provide evidence that Ectopic Calcification induced by CVB3 infection is implicated in the induction of osteogenic propensity, and α-lipoic acid may be a potential therapeutic agent to ameliorate pathologic Calcification.
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targeting of the osteoclastogenic rankl rank axis prevents osteoporotic bone loss and soft tissue Calcification in coxsackievirus b3 infected mice
Journal of Immunology, 2013Co-Authors: Ho Sun Park, Hoogeun Song, Hongin Shin, Hyun Kook, Jeonghyeon Ko, Daewon JeongAbstract:Bone mineralization is a normal physiological process, whereas Ectopic Calcification of soft tissues is a pathological process that leads to irreversible tissue damage. We have established a coxsackievirus B3 (CVB3)–infected mouse model that manifests both osteoporosis and Ectopic Calcification specifically in heart, pancreas, and lung. The CVB3-infected mice showed increased serum concentrations of both cytokines including IL-1β, TNF-α, and the receptor activator of NF-κB ligand (RANKL) that stimulate osteoclast formation and of the osteoclast-derived protein tartrate-resistant acid phosphatase 5b. They exhibited more osteoclasts in bone, with no change in the number of osteoblasts, and a decrease in bone formation and the serum concentration of osteoblast-produced osteocalcin. These results indicate that CVB3-induced osteoporosis is likely due to upregulation of osteoclast formation and function, in addition to decreased osteoblast activity. In addition, the serum in the CVB3-infected mice contained a high inorganic phosphate content, which causes Ectopic Calcification. RANKL treatment induced an increase in the in vitro cardiac fibroblast Calcification by inorganic phosphate via the upregulation of osteogenic BMP2, SPARC, Runx2, Fra-1, and NF-κB signaling. We finally observed that i.p. administration of RANK-Fc, a recombinant antagonist of RANKL, prevented bone loss as well as Ectopic Calcification in CVB3-infected mice. Thus, our results indicate that RANKL may contribute to both abnormal calcium deposition in soft tissues and calcium depletion in bone. In addition, our animal model should provide a tool for the development of new therapeutic agents for calcium disturbance in soft and hard tissues.
Ryoichi Matsuda - One of the best experts on this subject based on the ideXlab platform.
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effects of dietary phosphate on Ectopic Calcification and muscle function in mdx mice
2012Co-Authors: Eiji Wada, Namiko Kikkawa, Mizuko Yoshida, Munehiro Date, Tetsuo Higashi, Ryoichi MatsudaAbstract:Calcium deposits in extra-skeletal tissues are highly correlated with lifestyle diseases. The mechanisms and clinical effects of such deposition have been widely studied due to increase mortality rate. Vascular Calcification is a major complication in a number of diseases, including chronic kidney disease (CKD) and diabetes (Giachelli, 2009). The number of regulation mechanisms affecting calcium precipitation in soft tissues remains underestimated, as many regulators are considered to be involved in this complex process (Hu et al., 2010; Kendrick et al., 2011). Elevated serum phosphate levels which leads hyperphosphatemia is one of the prevalent factors of vascular Calcification in CKD (El-Abbadi et al., 2009). The kidneys play a central role in the regulation of phosphate homeostasis. In individuals with normal renal function, serum phosphate levels are strictly controlled through dietary intake, intestinal absorption, renal excretion, and bone metabolism. When the kidneys are either mechanically or functionally impaired, phosphate metabolism is imbalanced. Abnormalities of phosphate metabolism related to kidney malfunction may play a central role in the deposition of calcium and phosphate in extra-skeletal tissues. Ectopic Calcification in skeletal muscle has been reported to occur in three Duchenne muscular dystrophy (DMD) animal models; mdx mice (Coulton et al., 1987; Kikkawa et al., 2009), dystrophic puppies (Nguyen et al., 2002), and hypertrophic muscular dystrophy cats (Gaschen et al., 1992). In this chapter, we review the mechanisms of Ectopic Calcification in mdx mice and report a new finding of effects of dietary phosphate intake on calcium deposits and muscle function in mdx mice.
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Ectopic Calcification is caused by elevated levels of serum inorganic phosphate in mdx mice
Cell Structure and Function, 2009Co-Authors: Namiko Kikkawa, Tomohisa Ohno, Yosuke Nagata, Masataka Shiozuka, Toshihiro Kogure, Ryoichi MatsudaAbstract:Ectopic Calcification occurs in the skeletal muscle of mdx mice, a dystrophin-deficient animal model of Duchenne muscular dystrophy. The purpose of this study was to clarify the mechanism of the Calcification. The calcified deposits were identified as hydroxyapatite, a crystallized form of calcium phosphate, and the serum inorganic phosphate (Pi) level in the mdx mice was approximately 1.4 times higher than that in the normal B10 mice, suggesting that Pi plays a critical role in the Ectopic Calcification. When C2C12 mouse myoblasts were cultured under high-Pi conditions, myogenic differentiation was retarded while the expression of osteogenic markers such as osteocalcin and Runx2 were upregulated. This was followed by the generation of calcium deposition. Moreover, Ectopic Calcification reduced to an undetectable level in most of the mdx mice fed a Pi-reduced diet. We therefore conclude that the Pi-induced osteogenesis of muscle cells is responsible for Ectopic Calcification in the skeletal muscle of mdx mice.
Leon J Schurgers - One of the best experts on this subject based on the ideXlab platform.
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the role of chronic kidney disease in Ectopic Calcification
2020Co-Authors: Joanne Laycock, Leon J Schurgers, Malgorzata Furmanik, Mengxi Sun, Rukshana Shroff, Catherine M ShanahanAbstract:Dysregulated mineral metabolism and factors in uraemic serum place chronic kidney disease (CKD) patients at high risk of Ectopic Calcification, particularly vascular Calcification. CKD patients have impaired phosphate excretion accompanied by klotho deficiency and vitamin D deficiency. The parathyroid hormone and fibroblast growth factor 23 negative feedback loops are ineffective and over activated leading to secondary hyperparathyroidism, CKD bone mineral disorder and a chronic increase in calcium (Ca) and phosphate (P). High serum Ca and P drive several mechanisms of Calcification including apoptosis, osteogenic differentiation and the accumulation of both extracellular vesicles and calcium phosphate-containing particles (CPPs). Furthermore, the accumulation of uraemic toxins in serum has been shown to increase both oxidative and endoplasmic reticulum stress, which activate the inflammatory and DNA damage response pathways and promote Calcification. There is no cure for vascular Calcification, and treatment strategies involve preventing mineral dysregulation or directly targeting individual mechanisms of Calcification.
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Ectopic Calcification in β thalassemia patients is associated with increased oxidative stress and lower mgp carboxylation
Biochimica et Biophysica Acta, 2013Co-Authors: Federica Boraldi, M Garciafernandez, Chiara Paolinellidevincenzi, Giulia Annovi, Leon J Schurgers, Cees Vermeer, Paolo Cianciulli, Ivonne Ronchetti, Daniela QuaglinoAbstract:A number of beta-thalassemia (β-thal) patients in the course of the disease exhibit Ectopic Calcification affecting skin, eyes and the cardiovascular system. Clinical and histopathological features have been described similar to those in pseudoxanthoma elasticum (PXE), although different genes are affected in the two diseases. Cultured dermal fibroblasts from β-thal patients with and without PXE-like clinical manifestations have been compared for parameters of redox balance and for the expression of proteins, which have been already associated with the pathologic mineralisation of soft connective tissues. Even though oxidative stress is a well-known condition of β-thal patients, our results indicate that the occurrence of mineralized elastin is associated with a more pronounced redox disequilibrium, as demonstrated by the intracellular increase of anion superoxide and of oxidized proteins and lipids. Moreover, fibroblasts from β-thal PXE-like patients are characterized by decreased availability of carboxylated matrix Gla protein (MGP), as well as by altered expression of proteins involved in the vitamin K-dependent carboxylation process. Results demonstrate that elastic fibre Calcification is promoted when redox balance threshold levels are exceeded and the vitamin K-dependent carboxylation process is affected decreasing the activity of MGP, a well-known inhibitor of Ectopic Calcification. Furthermore, independently from the primary gene defect, these pathways are similarly involved in fibroblasts from PXE and from β-thal PXE-like patients as well as in other diseases leading to Ectopic Calcification, thus suggesting that can be used as markers of pathologic mineralisation.
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atypical presentation of pseudoxanthoma elasticum with abdominal cutis laxa evidence for a spectrum of Ectopic Calcification disorders
American Journal of Medical Genetics Part A, 2011Co-Authors: Olivier Vanakker, Leon J Schurgers, Cees Vermeer, Bart P Leroy, Paul Coucke, Anne De PaepeAbstract:A patient is presented with severe cutis laxa of the abdomen. Molecular investigations, including sequencing of the fibulin-5 and elastin gene, failed to endorse the diagnosis of inherited cutis laxa. Ultrasonographical discovery of renal Calcifications during his general work-up suggested a possible diagnosis of pseudo-xanthoma elasticum (PXE). A discrete yellowish reticular pattern in the anterior neck region was detected upon careful clinical examination. Clinically, the patient presented characteristics of both classic PXE (retinopathy, renal Calcifications) and the PXE-like syndrome (cutis laxa beyond the flexural areas). Skin biopsy and ophthalmological examination confirmed the diagnosis of PXE. In addition, ultrastructural evaluation revealed calcium deposits in the periphery of elastic fibers, a typical observation in the PXE-like syndrome. Immunohistochemical experiments and ELISA tests for various inhibitors of Calcification displayed results which were partly reminiscent of both PXE and the PXE-like syndrome. Molecular analysis revealed not only two ABCC6 mutations (related to PXE), but also a gain of function SNP in the GGCX gene, in which loss-of-function mutations cause the PXE-like syndrome. We conclude that the patients phenotype and--to a further extent--the PXE-like syndrome, are part of a spectrum of Ectopic Calcification disorders which are clinically and/or pathogenetically related to PXE. The molecular findings in this patient are however insufficient to explain the entire phenotype and suggest a role for multiple genetic factors in soft tissue mineralization.
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Vitamin K supplementation increases vitamin K tissue levels but fails to counteract Ectopic Calcification in a mouse model for pseudoxanthoma elasticum
Journal of Molecular Medicine, 2011Co-Authors: Theo G. M. F. Gorgels, Cees Vermeer, Jan H. Waarsing, Marjolein Herfs, Daniëlle Versteeg, Frank Schoensiegel, Toshiro Sato, Reinier O. Schlingemann, Boris Ivandic, Leon J SchurgersAbstract:Pseudoxanthoma elasticum (PXE) is an autosomal recessive disorder in which Calcification of connective tissue leads to pathology in skin, eye and blood vessels. PXE is caused by mutations in ABCC6 . High expression of this transporter in the basolateral hepatocyte membrane suggests that it secretes an as-yet elusive factor into the circulation which prevents Ectopic Calcification. Utilizing our Abcc6 ^−/− mouse model for PXE, we tested the hypothesis that this factor is vitamin K (precursor) (Borst et al. 2008, Cell Cycle). For 3 months, Abcc6 ^−/− and wild-type mice were put on diets containing either the minimum dose of vitamin K required for normal blood coagulation or a dose that was 100 times higher. Vitamin K was supplied as menaquinone-7 (MK-7). Ectopic Calcification was monitored in vivo by monthly micro-CT scans of the snout, as the PXE mouse model develops a characteristic connective tissue mineralization at the base of the whiskers. In addition, Calcification of kidney arteries was measured by histology. Results show that supplemental MK-7 had no effect on Ectopic Calcification in Abcc6 ^ −/− mice. MK-7 supplementation increased vitamin K levels (in skin, heart and brain) in wild-type and in Abcc6 ^−/− mice. Vitamin K tissue levels did not depend on Abcc6 genotype. In conclusion, dietary MK-7 supplementation increased vitamin K tissue levels in the PXE mouse model but failed to counteract Ectopic Calcification. Hence, we obtained no support for the hypothesis that Abcc6 transports vitamin K and that PXE can be cured by increasing tissue levels of vitamin K.
Rajesh V Thakker - One of the best experts on this subject based on the ideXlab platform.
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n ethyl n nitrosourea enu induced mutations within the klotho gene lead to Ectopic Calcification and reduced lifespan in mouse models
PLOS ONE, 2015Co-Authors: Christopher T Esapa, Fadil M Hannan, Valerie N Babinsky, Paul Potter, Gethin P Thomas, Peter I Croucher, Matthew A Brown, Steve D M Brown, Roger D Cox, Rajesh V ThakkerAbstract:Ectopic Calcification (EC), which is the pathological deposition of calcium and phosphate in extra-skeletal tissues, may be associated with hypercalcaemic and hyperphosphataemic disorders, or it may occur in the absence of metabolic abnormalities. In addition, EC may be inherited as part of several monogenic disorders and studies of these have provided valuable insights into the metabolic pathways regulating mineral metabolism. For example, studies of tumoural calcinosis, a disorder characterised by hyperphosphataemia and progressive EC, have revealed mutations of fibroblast growth factor 23 (FGF23), polypeptide N-acetyl galactosaminyltransferase 3 (GALNT3) and klotho (KL), which are all part of a phosphate-regulating pathway. However, such studies in humans are limited by the lack of available large families with EC, and to facilitate such studies we assessed the progeny of mice treated with the chemical mutagen N-ethyl-N-nitrosourea (ENU) for EC. This identified two mutants with autosomal recessive forms of EC, and reduced lifespan, designated Ecalc1 and Ecalc2. Genetic mapping localized the Ecalc1 and Ecalc2 loci to a 11.0 Mb region on chromosome 5 that contained the klotho gene (Kl), and DNA sequence analysis identified nonsense (Gln203Stop) and missense (Ile604Asn) Kl mutations in Ecalc1 and Ecalc2 mice, respectively. The Gln203Stop mutation, located in KL1 domain, was severely hypomorphic and led to a 17-fold reduction of renal Kl expression. The Ile604Asn mutation, located in KL2 domain, was predicted to impair klotho protein stability and in vitro expression studies in COS-7 cells revealed endoplasmic reticulum retention of the Ile604Asn mutant. Further phenotype studies undertaken in Ecalc1 (kl203X/203X) mice demonstrated elevations in plasma concentrations of phosphate, FGF23 and 1,25-dihydroxyvitamin D. Thus, two allelic variants of Kl that develop EC and represent mouse models for tumoural calcinosis have been established.
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activating calcium sensing receptor mutation in the mouse is associated with cataracts and Ectopic Calcification
Proceedings of the National Academy of Sciences of the United States of America, 2004Co-Authors: Tertius Hough, Debora Bogani, Michael Cheeseman, J Favor, Andrew M Nesbit, Rajesh V Thakker, Mary F LyonAbstract:The extracellular calcium-sensing receptor (CaSR) plays a pivotal role in the regulation of extracellular calcium such that abnormalities, which result in a loss or gain of function, lead to hypercalcemia or hypocalcemia, respectively, in patients. Mice carrying CaSR knockout alleles develop hypercalcemia that mimics the disorders observed in humans. To date, there is no mouse model for an activating CaSR mutation. Here, we describe such a mouse model, named Nuf, originally identified for having opaque flecks in the nucleus of the lens in a screen for eye mutants. Nuf mice also display Ectopic Calcification, hypocalcemia, hyperphosphatemia, and inappropriately reduced levels of plasma parathyroid hormone. These features are similar to those observed in patients with autosomal dominant hypocalcemia. Inheritance studies of Nuf mice revealed that the trait was transmitted in an autosomal-dominant manner, and mapping studies located the locus to chromosome 16, in the vicinity of the CaSR gene (Mouse Genome Database symbol Gprc2a). DNA sequence analysis revealed the presence of a Gprc2a missense mutation, Leu723Gln. Transient expression of wild-type and mutant CaSRs in human embryonic kidney 293 cells demonstrated that the mutation resulted in a gain of function of the CaSR, which had a significantly lower EC50. Thus, our results have identified a mouse model for an activating CaSR mutation, and the development of Ectopic Calcification and cataract formation, which tended to be milder in the heterozygote Nuf mice, indicates that an evaluation for such abnormalities in autosomal dominant hypocalcemia patients who have activating CaSR mutations is required.
