scholarly journals A variant in the CASR gene (c.368T>C) causing hypocalcemia refractory to standard medical therapy

2021 ◽  
Vol 2021 ◽  
Author(s):  
Diana Festas Silva ◽  
Adriana De Sousa Lages ◽  
Joana Serra Caetano ◽  
Rita Cardoso ◽  
Isabel Dinis ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Standard Therapy ◽  
Autosomal Dominant ◽  
Human Parathyroid Hormone ◽  
Calcium Sensing Receptor ◽  
Activating Mutations ◽  
Calcium Sensing ◽  
Clinical Stability ◽  
Autosomal Dominant Hypocalcemia

Summary Hypoparathyroidism is characterized by low or inappropriately normal parathormone production, hypocalcemia and hyperphosphatemia. Autosomal dominant hypocalcemia (ADH) type 1 is one of the genetic etiologies of hypoparathyroidism caused by heterozygous activating mutations in the calcium-sensing receptor (CASR) gene. Current treatments for ADH type 1 include supplementation with calcium and active vitamin D. We report a case of hypoparathyroidism in an adolescent affected by syncope without prodrome. The genetic testing revealed a variant in the CASR gene. Due to standard therapy ineffectiveness, the patient was treated with recombinant human parathyroid hormone (1–34), magnesium aspartate and calcitriol. He remained asymptomatic and without neurological sequelae until adulthood. Early diagnosis and treatment are important to achieve clinical stability. Learning points Autosomal dominant hypocalcemia (ADH) type 1 is one of the genetic etiologies of hypoparathyroidism caused by heterozygous activating mutations in the calcium-sensing receptor (CASR) gene. The variant c.368T>C (p.Leu123Ser) in heterozygosity in the CASR gene is likely pathogenic and suggests the diagnosis of ADH type 1. Teriparatide (recombinant human parathyroid hormone 1–34) may be a valid treatment option to achieve clinical stability for those individuals whose condition is poorly controlled by current standard therapy.

scholarly journals Novel Activating Mutations of the Calcium-Sensing Receptor: The Calcilytic NPS-2143 Mitigates Excessive Signal Transduction of Mutant Receptors

2010 ◽  
Vol 24 (9) ◽  
pp. 1888-1888
Author(s):  
Saskia Letz ◽  
Ramona Rus ◽  
Christine Haag ◽  
Helmuth-Günther Dörr ◽  
Dirk Schnabel ◽  
...  
Keyword(s):  
Autosomal Dominant ◽  
Functional Characterization ◽  
Calcium Excretion ◽  
Wild Type ◽  
Calcium Sensing Receptor ◽  
Activating Mutations ◽  
Calcium Sensing ◽  
Mutant Receptors ◽  
Autosomal Dominant Hypocalcemia

Abstract Context and Objective: Activating mutations in the calcium-sensing receptor (CaSR) gene cause autosomal dominant hypocalcemia (ADH). The aims of the present study were the functional characterization of novel mutations of the CaSR found in patients, the comparison of in vitro receptor function with clinical parameters, and the effect of the allosteric calcilytic NPS-2143 on the signaling of mutant receptors as a potential new treatment for ADH patients. Methods: Wild-type and mutant CaSR (T151R, P221L, E767Q, G830S, and A844T) were expressed in human embryonic kidney cells (HEK 293T). Receptor signaling was studied by measuring intracellular free calcium in response to different concentrations of extracellular calcium ([Ca2+]o) in the presence or absence of NPS-2143. Results: All ADH patients had lowered serum calcium ranging from 1.7 to 2.0 mm and inadequate immunoreactive PTH and urinary calcium excretion. In vitro testing of CaSR mutations from these patients revealed exaggerated [Ca2+]o-induced cytosolic Ca2+ responses with EC50 values for [Ca2+]o ranging from 1.56 to 3.15 mm, which was lower than for the wild-type receptor (4.27 mm). The calcilytic NPS-2143 diminished the responsiveness to [Ca2+]o in the CaSR mutants T151R, E767Q, G830S, and A844T. The mutant P221L, however, was only responsive when coexpressed with the wild-type CaSR. Conclusion: Calcilytics might offer medical treatment for patients with autosomal dominant hypocalcemia caused by calcilytic-sensitive CaSR mutants.

Three Novel Activating Mutations in the Calcium-Sensing Receptor Responsible for Autosomal Dominant Hypocalcemia

2000 ◽  
Vol 71 (4) ◽  
pp. 591-598 ◽  
Author(s):  
Yvette P. Conley ◽  
David N. Finegold ◽  
David G. Peters ◽  
Jennifer S. Cook ◽  
Daniel S. Oppenheim ◽  
...  
Keyword(s):  
Autosomal Dominant ◽  
Calcium Sensing Receptor ◽  
Activating Mutations ◽  
Calcium Sensing ◽  
Autosomal Dominant Hypocalcemia

scholarly journals A novel mutation in the calcium-sensing receptor responsible for autosomal dominant hypocalcemia in a family with two uncommon parathyroid hormone polymorphisms

2003 ◽  
Vol 31 (2) ◽  
pp. 255-262 ◽  
Author(s):  
D Alvarez-Hernandez ◽  
I Santamaria ◽  
M Rodriguez-Garcia ◽  
P Iglesias ◽  
R Delgado-Lillo ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Intracellular Signaling ◽  
Autosomal Dominant ◽  
Novel Mutation ◽  
Polymorphism Analysis ◽  
Calcium Sensing Receptor ◽  
Amino Terminal ◽  
Rich Domain ◽  
Calcium Sensing ◽  
Autosomal Dominant Hypocalcemia

A novel missense activating mutation in the extracellular calcium-sensing receptor (CaSR) is reported in this work. It was identified in three related subjects with the phenotypic features of autosomal dominant hypocalcemia (ADH). The proband, a 27-year-old woman, diagnosed as having hypoparathyroidism at 7 years of age and a history of seizures, showed the highest penetrance of the mutation. The remaining two affected members presented asymptomatic chronic hypocalcemia despite severe hypoparathyroidism associated with high levels of serum phosphate and calcium urinary excretion. The missense mutation (Glu(604)Lys) affected an amino acid residue in the C terminus of the cysteine-rich domain of the extracellular amino-terminal domain, which seems to be required for the coupling of ligand binding to the activation of intracellular signaling pathways. This genetic change cosegregated with hypocalcemia in all the individuals where the mutation was found. As parathyroid hormone (PTH) secretion is the regulatory target of the CaSR, polymorphism analysis of the PTH gene was carried out. PTH polymorphisms were analyzed in the kindred studied. Affected members for the Glu(604)Lys CaSR mutation which also carried the uncommon PTH alleles showed higher penetrance of the mutation, with more severe autosomal dominant hypocalcemia. These results suggested that the PTH gene could act as a modifier locus of ADH, affecting the penetrance of the activating CaSR mutation described.

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