scholarly journals Calcium Signaling Regulates Trafficking of Familial Hypocalciuric Hypercalcemia (FHH) Mutants of the Calcium Sensing Receptor

2012 ◽  
Vol 26 (12) ◽  
pp. 2081-2091 ◽  
Author(s):  
Michael P. Grant ◽  
Ann Stepanchick ◽  
Gerda E. Breitwieser
Keyword(s):  
Plasma Membrane ◽  
Steady State ◽  
State Level ◽  
Membrane Targeting ◽  
Familial Hypocalciuric Hypercalcemia ◽  
Loss Of Function ◽  
Wild Type ◽  
Calcium Sensing Receptor ◽  
Dynamic Changes ◽  
Calcium Sensing

Abstract Calcium-sensing receptors (CaSRs) regulate systemic Ca2+ homeostasis. Loss-of-function mutations cause familial benign hypocalciuric hypercalcemia (FHH) or neonatal severe hyperparathyroidism (NSHPT). FHH/NSHPT mutations can reduce trafficking of CaSRs to the plasma membrane. CaSR signaling is potentiated by agonist-driven anterograde CaSR trafficking, leading to a new steady state level of plasma membrane CaSR, which is maintained, with minimal functional desensitization, as long as extracellular Ca2+ is elevated. This requirement for CaSR signaling to drive CaSR trafficking to the plasma membrane led us to reconsider the mechanism(s) contributing to dysregulated trafficking of FHH/NSHPT mutants. We simultaneously monitored dynamic changes in plasma membrane levels of CaSR and intracellular Ca2+, using a chimeric CaSR construct, which allowed explicit tracking of plasma membrane levels of mutant or wild-type CaSRs in the presence of nonchimeric partners. Expression of mutants alone revealed severe defects in plasma membrane targeting and Ca2+ signaling, which were substantially rescued by coexpression with wild-type CaSR. Biasing toward heterodimerization of wild-type and FHH/NSHPT mutants revealed that intracellular Ca2+ oscillations were insufficient to rescue plasma membrane targeting. Coexpression of the nonfunctional mutant E297K with the truncation CaSRΔ868 robustly rescued trafficking and Ca2+ signaling, whereas coexpression of distinct FHH/NSHPT mutants rescued neither trafficking nor signaling. Our study suggests that rescue of FHH/NSHPT mutants requires a steady state intracellular Ca2+ response when extracellular Ca2+ is elevated and argues that Ca2+ signaling by wild-type CaSRs rescues FHH mutant trafficking to the plasma membrane.

Heterozygous Mutation (Q459R) in the Calcium-Sensing Receptor Gene Causes Familial Hypocalciuric Hypercalcemia 1 (FHH1)

2019 ◽  
Vol 105 (4) ◽  
pp. e1322-e1330 ◽  
Author(s):  
Ida Marie Boisen ◽  
Iris Mos ◽  
Eva Merete Lerche-Black ◽  
Anders Juul ◽  
Hans Bräuner-Osborne ◽  
...  
Keyword(s):  
Receptor Gene ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Familial Hypocalciuric Hypercalcemia ◽  
Loss Of Function ◽  
Wild Type ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing ◽  
Calcium Sensing Receptor Gene

Abstract Context Several heterozygous loss-of-function mutations in the calcium-sensing receptor gene (CASR) leading to elevated ionized serum calcium and familial hypocalciuric hypercalcemia 1 (FHH1) have been characterized. Few mutations are not pathogenic, and previous studies suggested that the Q459R mutation does not result in an FHH1 phenotype. Objective We identified a family with a heterozygous CASR Q459R mutation and characterized their calcium homeostasis and the pathophysiological mechanisms of a homozygous and heterozygous Q459R mutation in vitro. Design The index patient and her family had clinical, biochemical, and genetic analyses performed. In vitro functional characterization of homozygous and heterozygous (Q459R) mutations was conducted by determining CaSR cell-surface expression and inositol monophosphate (IP1) signaling in transiently transfected human embryonic kidney 293A (HEK293A) cells. Results All 3 heterozygous carriers had mild asymptomatic hypercalcemia, hypocalciuria, and 2 had elevated serum parathyroid hormone (PTH). In vitro characterization in HEK293A cells revealed that CASR Q459R is a loss-of-function mutation with no impact on cell-surface expression. Cells with the homozygous Q459R genotype had significantly reduced calcium potency of IP1 signaling compared to wild type, whereas the heterozygous Q459R also had lower calcium potency albeit not significantly different from wild type. Conclusion A loss-of-function Q459R mutation in CASR in a family caused FHH1 characterized by elevated ionized calcium and PTH and low calcium excretion. The marked presence of CaSR at the membrane and inhibition of IP1 signaling in vitro suggest that calcimimetics may be functional in patients with this mutation, which seems to be a mild loss-of-function mutation associated with autosomal dominant transmission of FHH1.

scholarly journals SAT-404 Neonatal Hypocalcemic Seizures in Offspring of a Mother with Familial Hypocalciuric Hypercalcemia Type 1 (FHH1)

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Fadil M Hannan ◽  
Poonam Dharmaraj ◽  
Caroline M Gorvin ◽  
Astha Soni ◽  
Nick D Nelhans ◽  
...  
Keyword(s):  
Serum Calcium ◽  
Mutational Analysis ◽  
Mitogen Activated Protein Kinase ◽  
Hek293 Cells ◽  
Familial Hypocalciuric Hypercalcemia ◽  
Loss Of Function ◽  
Calcium Sensing Receptor ◽  
Benign Condition ◽  
Calcium Sensing

Abstract Background: Familial hypocalciuric hypercalcemia type 1 (FHH1) is caused by loss-of-function mutations of the calcium-sensing receptor (CaSR), and considered to be a benign condition associated with mild-to-moderate hypercalcemia (1). However, the children of parents with FHH1 can develop a variety of disorders of calcium homeostasis in infancy. Objective: To further characterise the range of calcitropic phenotypes in the children of a mother with FHH1. Methods: We assessed a three generation FHH kindred by clinical, biochemical and mutational analysis following informed consent. Results: The kindred comprised a hypercalcemic male, his daughter who had hypercalcemia and hypocalciuria, and her four children, of whom two had asymptomatic hypercalcemia, one was normocalcemic, and one suffered from transient hypocalcemic seizures during infancy. The hypocalcemic infant had a serum calcium of 1.57 mmol/L (normal, 2.0-2.8) and PTH of 2.2 pmol/L (normal, 1.0-9.3) as a consequence of maternal hypercalcemia, and required treatment with I-V calcium gluconate infusions. Mutational analysis identified a novel heterozygous p.Ser448Pro CaSR variant in the hypercalcemic family members, but not in the children with hypocalcemia or normocalcemia. Three-dimensional modelling using a reported crystal structure of the dimeric CaSR showed the mutated Ser448 residue to be located in the CaSR extracellular domain, and predicted the p.Ser448Pro variant to disrupt a hydrogen bond interaction across the extracellular CaSR dimer interface. The variant Pro448 CaSR, when expressed in HEK293 cells, was shown to significantly impair CaSR-mediated intracellular calcium mobilisation and mitogen-activated protein kinase (MAPK) responses following stimulation with extracellular calcium, thereby demonstrating it to represent a loss-of-function mutation. Conclusion: These studies have identified a novel loss-of-function CaSR mutation which caused asymptomatic hypercalcemia in a mother and her children who had inherited the mutation. However, one child who did not inherit the mutation developed transient neonatal hypocalcemic seizures as a consequence of maternal hypercalcemia. These findings highlight the importance of assessing serum calcium and undertaking CaSR mutational analysis in the newborn offspring of a mother with FHH1. Reference: (1) Hannan FM, Kallay E, Chang W, Brandi ML, Thakker RV. The calcium-sensing receptor in physiology and in calcitropic and noncalcitropic diseases. Nat Rev Endocrinol. 2018; 15(1): 33-51.

scholarly journals SAT-351 A Novel Mutation in the Calcium-Sensing Receptor Gene Presenting in a Kindred as Autosomal Dominant Familial Hypocalciuric Hypercalcemia

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Jordan Bushman ◽  
Ajaz Banka
Keyword(s):  
Genetic Analysis ◽  
Novel Mutation ◽  
Receptor Gene ◽  
Family Members ◽  
Heterozygous Mutation ◽  
Familial Hypocalciuric Hypercalcemia ◽  
Loss Of Function ◽  
Calcium Sensing Receptor ◽  
Casr Gene ◽  
Calcium Sensing

Abstract Rationale: Familial hypocalciuric hypercalcemia (FHH) is a benign cause of hypercalcemia. The majority of cases result from an inactivating mutation in the calcium-sensing receptor (CaSR). While affected patients are usually asymptomatic and require no treatment, this condition may go unrecognized and inappropriate parathyroidectomy for presumed primary hyperparathyroidism could be performed. Over 130 mutations in the CaSR gene have been reported and novel variants continue to emerge. Methods: The initial patient was a 49 year-old female who presented with mild hypercalcemia, elevated PTH and undetectable urine calcium. She reported several of her family members had elevated calcium levels. Given high clinical suspicion for FHH genetic analysis was performed. Results: Sequencing of the CaSR gene revealed a point mutation at c.1744T>A which resulted in p.Cys582Ser in exon 7. This cystine residue is highly conserved and predictive algorithms suggest this variant is likely disruptive leading to heterozygous loss of function in the CaSR. The patient’s 26 year-old daughter was tested and found to have the same mutation. Conclusion: We report the identification of a novel heterozygous mutation in the CaSR gene manifesting as FHH in a family of Iraqi decent. Additional family members are currently undergoing genetic analysis which will be included at the time of presentation.

scholarly journals A Novel Loss-of-Function Mutation, Gln459Arg, of the Calcium-Sensing Receptor Gene Associated with Apparent Autosomal Recessive Inheritance of Familial Hypocalciuric Hypercalcemia

2009 ◽  
Vol 94 (11) ◽  
pp. 4372-4379 ◽  
Author(s):  
Steven A. Lietman ◽  
Yardena Tenenbaum-Rakover ◽  
Tjin Shing Jap ◽  
Wu Yi-Chi ◽  
Yang De-Ming ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Biochemical Characterization ◽  
Autosomal Recessive Inheritance ◽  
Recessive Inheritance ◽  
Familial Hypocalciuric Hypercalcemia ◽  
Loss Of Function ◽  
Calcium Sensing Receptor ◽  
Casr Gene ◽  
Calcium Sensing ◽  
Inactivating Mutation

Context: Mutations that inactivate one allele of the gene encoding the calcium sensing receptor (CaSR) cause autosomal dominant familial hypocalciuric hypercalcemia (FHH), whereas homozygous mutations cause neonatal severe hyperparathyroidism. Objective: We describe the identification and biochemical characterization of a novel CASR gene mutation that caused apparent autosomal recessive FHH in an extended consanguineous kindred. Design: The study design involved direct sequence analysis of the CaSR gene, clinical and biochemical analyses of patients, and in vitro immunobiochemical studies of the mutant CaSR. Results: A novel inactivating mutation (Q459R) was identified in exon 4 of both alleles of the CASR in the proband, who presented with asymptomatic hypercalcemia and hypocalciuria at age 2 yr. The proband’s parents were heterozygous for the Q459R mutation consistent with autosomal recessive inheritance of FHH. Among 13 family members that were studied, eight subjects were heterozygous for the Q459R mutation and five had normal genotypes. All heterozygous subjects were asymptomatic and normocalcemic apart from one subject who was mildly hypercalcemic. The Q459R mutant CaSR was normally expressed at the cell membrane but retained only 30–50% of the calcium-dependent activity of the wild-type CaSR. Conclusion: We identified a novel loss-of-function Q459R mutation in the CASR gene that exhibits mildly reduced sensitivity to calcium and that is associated with apparent autosomal recessive transmission of FHH. This study demonstrates the importance of genetic testing in FHH to distinguish between de novo and inherited mutations of the CASR gene and assist in management decisions. An extended kindred with familial hypocalciuric hypercalcemia possessed a novel inactivating mutation of the CaSR with highly variable biochemical phenotypes and apparent autosomal recessive inheritance.

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