ArticleThe Journal of clinical endocrinology and metabolism2018
Homozygous Calcium-Sensing Receptor Polymorphism R544Q Presents as Hypocalcemic Hypoparathyroidism.
Article in The Journal of clinical endocrinology and metabolism, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 26 citations in OpenAlex.
- Clinical and genetic insights into Autosomal Dominant Hypocalcemia type 1: a single-center case series including genotype-phenotype correlations, pregnancy outcomes, and novel CASR variants.Journal of endocrinological investigation · 2026Article
- Prevalence of loss-of-function, gain-of-function and dominant-negative mechanisms across genetic disease phenotypes.Nature communications · 2025Article
- Analysis of Calcium-Sensing Receptor Signaling Using Dual Luciferase Assays.Methods in molecular biology (Clifton, N.J.) · 2025Article
- Monitoring Calcium-Sensing Receptor (CaSR)-Induced Intracellular Calcium Flux Using an Indo-1 Flow Cytometry Assay.Methods in molecular biology (Clifton, N.J.) · 2025Article
- Induced Muscle and Liver Absence of Gne in Postnatal Mice Does Not Result in Structural or Functional Muscle Impairment.Journal of neuromuscular diseases · 2024Article
- Buffering of genetic dominance by allele-specific protein complex assembly.Science advances · 2023Article
- Autosomal dominant hypocalcemia with a novelThe Journal of international medical research · 2022Review
- The Importance of Functionally Characterizing Calcium-Sensing Receptor Variants in Individuals With Hypercalcemia.Journal of the Endocrine Society · 2022Review
- Human Disease Phenotypes Associated with Loss and Gain of Function Mutations in STAT2: Viral Susceptibility and Type I Interferonopathy.Journal of clinical immunology · 2021Review
- International Union of Basic and Clinical Pharmacology. CVIII. Calcium-Sensing Receptor Nomenclature, Pharmacology, and Function.Pharmacological reviews · 2020Review
- Homozygous STAT2 gain-of-function mutation by loss of USP18 activity in a patient with type I interferonopathy.The Journal of experimental medicine · 2020Article
- Article
- HomozygousProceedings of the National Academy of Sciences of the United States of America · 2019Article
- Letter to the Editor: "A Unique Case of Metastatic, Functional, Hereditary Paraganglioma Associated With an SDHC Germline Mutation".The Journal of clinical endocrinology and metabolism · 2019Article
- A Gain-of-Function CASR Mutation Causing Hypocalcemia in a Recessive Manner.The Journal of clinical endocrinology and metabolism · 2018Article
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Authors and funding
12 authors at 3 institutions in 2 countries.
Funding
Abstract
Context: Autosomal dominant hypocalcemia type 1 (ADH1) is caused by heterozygous activating mutations in the calcium-sensing receptor gene (CASR). Whether polymorphisms that are benign in the heterozygous state pathologically alter receptor function in the homozygous state is unknown. Objective: To identify the genetic defect in an adolescent female with a history of surgery for bilateral cataracts and seizures. The patient has hypocalcemia, hyperphosphatemia, and low serum PTH level. The parents of the proband are healthy. Methods: Mutation testing of PTH, GNA11, GCM2, and CASR was done on leukocyte DNA of the proband. Functional analysis in transfected cells was conducted on the gene variant identified. Public single nucleotide polymorphism (SNP) databases were searched for the presence of the variant allele. Results: No mutations were identified in PTH, GNA11, and GCM2 in the proband. However, a germline homozygous variant (c.1631G>A; p.R544Q) in exon 6 of the CASR was identified. Both parents are heterozygous for the variant. The variant allele frequency was near 0.1% in SNP databases. By in vitro functional analysis, the variant was significantly more potent in stimulating both the Ca2+i and MAPK signaling pathways than wild type when transfected alone (P < 0.05) but not when transfected together with wild type. The overactivity of the mutant CaSR is due to loss of a critical structural cation-π interaction. Conclusions: The patient's hypoparathyroidism is due to homozygosity of a variant in the CASR that normally has weak or no phenotypic expression in heterozygosity. Although rare, this has important implications for genetic counseling and clinical management.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.