Loss-of-Function Thr347Ala Variant in the G Protein Subunit-α11 Causes Familial Hypocalciuric Hypercalcemia 2 (FHH2)

Ida Marie Boisen, Wei Du, Anders Juul, Hans Bräuner-Osborne, Anders A Jensen, Martin Blomberg Jensen*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

CONTEXT AND OBJECTIVES: To date, only four loss-of-function variants in the GNA11 gene encoding the G protein subunit α11 (Gα11) leading to familial hypocalciuric hypercalcemia 2 (FHH2) have been characterized. Gα11 is involved in calcium-sensing receptor (CaSR) signaling, and loss-of-function variants in GNA11 lead to reduced agonist potency at CaSR and an FHH phenotype.

DESIGN AND PARTICIPANTS: We have identified a family with a heterozygous GNA11 Thr347Ala variant and characterized its impact on calcium homeostasis in FHH2 patients and the signaling properties of CaSR through the Gα11-Thr347Ala variant in vitro.

MAIN OUTCOME MEASURES: The index patient and her family had clinical, biochemical, and genetic analyses performed. The expression levels of Gα11 and the cell-surface expression levels of CaSR in human embryonic kidney 293A Gq/11 knock-out cells (ΔGq/11-HEK293A) co-transfected with CaSR and Gα11 (wild type (WT) or Thr347Ala) were determined, and the functional properties exhibited by calcium at CaSR were characterized in an inositol monophosphate (IP1) accumulation assay.

RESULTS: Heterozygous carriers of the GNA11 Thr347Ala variant had mild asymptomatic hypercalcemia, hypocalciuria, and inappropriately high normal parathyroid hormone (PTH) levels considering their elevated serum calcium levels. Whereas the variant did not impact Gα11 expression or CaSR cell surface expression levels, calcium displayed a moderately but significantly lower agonist potency at CaSR/Gα11-Thr347Ala-transfected cells compared with CaSR/Gα11-WT-transfected cells in the IP1 accumulation assay (EC50 values of 5.67 mM and 4.38 mM, respectively).

CONCLUSIONS: This identification of a novel GNA11 variant causing FHH2 substantiates the important role of Gα11 for CaSR signaling and Ca2+ homeostasis.

Original languageEnglish
JournalThe Journal of clinical endocrinology and metabolism
ISSN0021-972X
DOIs
Publication statusE-pub ahead of print - 2024

Bibliographical note

© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact [email protected] for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact [email protected]. See the journal About page for additional terms.

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