Identification and characterization of D410E, a novel mutation in the loop 3 domain of <scp>CASR</scp>, in autosomal dominant hypocalcemia and a therapeutic approach using a novel calcilytic, <scp>AXT</scp>914

Park, So Young; Mun, Hee-Chang; Eom, Young Sil; Baek, Hae Lim; Jung, Tae Sik; Kim, Chul Hoon; Lee, Sihoon

doi:10.1111/cen.12056

Cited by 14 publications

(9 citation statements)

References 28 publications

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“…Calcilytics may indeed be employed in conditions characterized by hypocalcemia and inappropriately low PTH levels, such as ADH, caused by activating mutation of the CaSR, since they revert the abnormal set point for systemic calcium homeostasis [103,104]. In this setting, CaSR antagonists mainly act through preserving calcium eliciting paracellular calcium transport through the thick Fig.…”

Section: Calcilytics: Effects On Bonementioning

confidence: 99%

The calcium-sensing receptor in bone metabolism: from bench to bedside and back

et al. 2015

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Calcium released in the bone microenvironment during remodeling is a major factor in regulating bone cells. Osteoblast and osteoclast proliferation, differentiation, and apoptosis are influenced by local extracellular calcium concentration. Thus, the calcium-sensing properties of skeletal cells can be exploited in order to modulate bone turnover and can explain the bone anabolic effects of agents developed and employed to revert osteoporosis.

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Section: Calcilytics: Effects On Bonementioning

confidence: 99%

The calcium-sensing receptor in bone metabolism: from bench to bedside and back

et al. 2015

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“…Calcimimetics are right now used to treat primary or secondary hyperparathyroidism conditions and to rescue loss-of function CaSR mutants. Conversely, calcilytics were initially meant (but till now not clinically used) to treat osteoporosis and may mitigate the effects of gain-of-function CaSR mutants [ 66 - 73 ]. Finally, it is worth recalling that the CaSR exhibits several distinct conformational states, each of which is induced and stabilized by a different ligand, allosteric agonists and antagonists included, and is linked to a particular set of intracellular signaling pathways—a property defined “ ligand-biased signaling ” [ 74 ] .…”

Section: Structure Signaling Agonists and Antagonists Of The Casrmentioning

confidence: 99%

Calcium-Sensing Receptors of Human Astrocyte-Neuron Teams: Amyloid-β-Driven Mediators and Therapeutic Targets of Alzheimer’s Disease

Prà¹,

Chiarini²,

Pacchiana

et al. 2014

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It is generally assumed that the neuropathology of sporadic (late-onset or nonfamilial) Alzheimer’s disease (AD) is driven by the overproduction and spreading of first Amyloid-βx-42 (Aβ42) and later hyperphosphorylated (hp)-Tau oligomeric “infectious seeds”. Hitherto, only neurons were held to make and spread both oligomer types; astrocytes would just remove debris. However, we have recently shown that exogenous fibrillar or soluble Aβ peptides specifically bind and activate the Ca2+-sensing receptors (CaSRs) of untransformed human cortical adult astrocytes and postnatal neurons cultured in vitro driving them to produce, accrue, and secrete surplus endogenous Aβ42. While the Aβ-exposed neurons start dying, astrocytes survive and keep oversecreting Aβ42, nitric oxide (NO), and vascular endothelial growth factor (VEGF)-A. Thus astrocytes help neurons’ demise. Moreover, we have found that a highly selective allosteric CaSR agonist (“calcimimetic”), NPS R-568, mimics the just mentioned neurotoxic actions triggered by Aβ●CaSR signaling. Contrariwise, and most important, NPS 2143, a highly selective allosteric CaSR antagonist (“calcilytic”), fully suppresses all the Aβ●CaSR signaling-driven noxious actions. Altogether our findings suggest that the progression of AD neuropathology is promoted by unceasingly repeating cycles of accruing exogenous Aβ42 oligomers interacting with the CaSRs of swelling numbers of astrocyte-neuron teams thereby recruiting them to overrelease additional Aβ42 oligomers, VEGF-A, and NO. Calcilytics would beneficially break such Aβ/CaSR-driven vicious cycles and hence halt or at least slow the otherwise unstoppable spreading of AD neuropathology

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“…8 in Table 4), which we reported as a novel mutation in the previous study (13). Another mutation of the CASR gene (c.662C>T [P221L]) was detected in one family (patient No.…”

Section: Resultsmentioning

confidence: 67%

“…IH is a heterogeneous group of disorders with various genetic mutations; mainly PTH and CASR genes affecting PTH secretion, and GCMB genes related to parathyroid embryogenesis (15). In our series, IH results from three different mutations which have been described in the literature (P221L in the CASR gene) (14), including two by our group (C106R in the GCMB gene and D410E in the CASR gene) (11, 13). We showed that IH patients possessed several SNPs in the PTH , CASR , or GCMB genes regardless of accompanying functional mutations.…”

Section: Discussionmentioning

confidence: 80%

Genetic and Clinical Characteristics of Korean Patients with Isolated Hypoparathyroidism: From the Korean Hypopara Registry Study

et al. 2013

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Isolated hypoparathyroidism (IH) shows heterogeneous phenotypes and can be caused by defects in a variety of genes. The goal of our study was to determine the clinical features and to analyze gene mutations in a large cohort of Korean patients with sporadic or familial IH. We recruited 23 patients. They showed a broad range of onset age and various values of biochemical data. Whole exome sequencing was performed on two affected cases and one unaffected individual in a family. All coding exons and exon-intron borders of GCMB, CASR, and prepro-PTH were sequenced using PCR-amplified DNA. In one family who underwent the whole exome sequencing analysis, approximately 300 single nucleotide changes emerged as candidates for genetic alteration. Among them, we identified a functional mutation in exon 2 of GCMB (C106R) in two affected cases. Besides, heterozygous gain-of-function mutations in the CASR gene were found in other subjects; D410E and P221L. We also found one single nucleotide polymorphism (SNP) in the prepro-PTH gene, five SNPs in the CASR gene, and four SNPs in the GCMB gene. The current study represents a variety of biochemical phenotypes in IH patients with the molecular genetic diagnosis of IH.

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Identification and characterization of D410E, a novel mutation in the loop 3 domain of CASR, in autosomal dominant hypocalcemia and a therapeutic approach using a novel calcilytic, AXT914

Cited by 14 publications

References 28 publications

The calcium-sensing receptor in bone metabolism: from bench to bedside and back

The calcium-sensing receptor in bone metabolism: from bench to bedside and back

Calcium-Sensing Receptors of Human Astrocyte-Neuron Teams: Amyloid-β-Driven Mediators and Therapeutic Targets of Alzheimer’s Disease

Genetic and Clinical Characteristics of Korean Patients with Isolated Hypoparathyroidism: From the Korean Hypopara Registry Study

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