Abstract Context Autosomal dominant hypocalcemia type 1 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 not known. Objective To identify the genetic defect in an adolescent female with a past history of surgery for bilateral cataracts and seizures. The patient has hypocalcemia, hyperphosphatemia and low serum parathyroid hormone (PTH) levels. 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 SNP databases were interrogated 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. Copyright © 2018 Endocrine Society
Journal of Clinical Endocrinology and Metabolism – Oxford University Press
Published: May 25, 2018
It’s your single place to instantly
discover and read the research
that matters to you.
Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.
All for just $49/month
Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly
Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.
All the latest content is available, no embargo periods.
“Whoa! It’s like Spotify but for academic articles.”@Phil_Robichaud