Homozygous Calcium-Sensing Receptor Polymorphism R544Q Presents as Hypocalcemic Hypoparathyroidism

The Journal of Clinical Endocrinology and Metabolism
Branca CavacoGeoffrey N Hendy

Abstract

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. 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. 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. 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....Continue Reading

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Citations

Oct 26, 2018·The Journal of Clinical Endocrinology and Metabolism·Fady Hannah-Shmouni, Roberto Londo-Mendoza
Jul 19, 2018·The Journal of Clinical Endocrinology and Metabolism·Murat Bastepe
Sep 6, 2019·Proceedings of the National Academy of Sciences of the United States of America·Scott B DrutmanJean-Laurent Casanova
Feb 25, 2020·The Journal of Experimental Medicine·Conor GruberDusan Bogunovic
Aug 28, 2021·Journal of Clinical Immunology·Christopher James Arthur Duncan, Sophie Hambleton

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