Homozygous calcium-sensing receptor polymorphism R544Q presents as hypocalcemic hypoparathyroidism

Homozygous calcium-sensing receptor polymorphism R544Q presents as hypocalcemic hypoparathyroidism 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 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Clinical Endocrinology and Metabolism Oxford University Press

Loading next page...
 
/lp/ou_press/homozygous-calcium-sensing-receptor-polymorphism-r544q-presents-as-w2w0peoGub
Publisher
Endocrine Society
Copyright
Copyright © 2018 Endocrine Society
ISSN
0021-972X
eISSN
1945-7197
D.O.I.
10.1210/jc.2017-02407
Publisher site
See Article on Publisher Site

Abstract

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

Journal of Clinical Endocrinology and MetabolismOxford University Press

Published: May 25, 2018

There are no references for this article.

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

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

Explore the DeepDyve Library

Search

Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly

Organize

Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.

Access

Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve

Freelancer

DeepDyve

Pro

Price

FREE

$49/month
$360/year

Save searches from
Google Scholar,
PubMed

Create lists to
organize your research

Export lists, citations

Read DeepDyve articles

Abstract access only

Unlimited access to over
18 million full-text articles

Print

20 pages / month

PDF Discount

20% off