OR43-4 Germline Mutations in G Protein Alpha 11 Cause Autosomal-Dominant Hypoparathyroidism

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR43-Disorders of Calcium Homeostasis
Tuesday, June 18, 2013: 9:15 AM-10:45 AM
Presentation Start Time: 10:00 AM
Room 122 (Moscone Center)
Michael Mannstadt*1, Mark Harris2, Bert Bravenboer3, Sridhar Chitturi4, Koen Dreijerink5, David Lambright6, Elaine Lim7, Mark Daly7, Stacey Gabriel8 and Harald W Jueppner7
1Massachusetts General Hospital and Harvard Medical School, Boston, MA, 2Mater Children's Hosp, Ashgrove QLD, Australia, 3Catharina Hosp, Eindhoven, Netherlands, 4Consultant Endocrinologist, Casuarina, NT, Australia, 5University Medical Center Utrecht, Utrecht, Netherlands, 6UMASS Medical School, Worcester, MA, 7Massachusetts General Hospital, Boston, MA, 8The Broad Institute, Cambridge, MA
Hypoparathyroidism, characterized by insufficient secretion of parathyroid hormone and hypocalcemia, is genetically heterogeneous.  Mutations in the genes encoding PTH, the parathyroid-specific transcription factor GCM2, or the calcium-sensing receptor (CaSR) can all cause non-syndromic, isolated hypoparathyroidism (IHP).  However, for the majority of patients with IHP, the underlying molecular defect is unknown.

We studied two large, unrelated Caucasian families in which affected members (n=15) had mild symptoms of hypocalcemia and the typical biochemical constellation of hypoparathyroidism: hypocalcemia, hyperphosphatemia and low PTH levels. In the index cases of both families, we excluded mutations in the three candidate genes PTH, GCM2 and CaSR by Sanger sequencing.  To identify the genetic defect, a combination of genome-wide linkage analysis and exome sequencing was utilized.  In family A, a single peak of linkage on chromosome 19p13.3 (LOD score 3.0) was identified. Within the linked region, only one mutation was revealed by exome sequencing of two affected members of family A: a novel missense mutation in exon 2 of GNA11, which encodes the α-subunit of the heterotrimeric G protein 11 (Gα11).  In family B, exome sequencing of two affected members revealed a distinct heterozygous missense mutation in exon 5 of GNA11. Both Gα11 mutations, which affect highly conserved amino acid residues, were found in all affected members of the respective family, but were absent in the available unaffected members and not found in the databases. 

Gα11 and the related Gαq mediate signaling down-stream of the CaSR, which is the main regulator of synthesis and secretion of PTH by the parathyroid glands. The identified mutations are predicted to lead to a gain-of-function, similar to activating heterozygous CaSR mutations that result in autosomal dominant hypoparathyroidism.  Consistent with this conclusion, modeling using the crystal structure of Gαq indicated that introducing the R60C and the S211W mutation causes significant functional changes. Arg60, located in α1 of the GTPase domain, forms an intramolecular hydrogen bond with Asp71 of the helical domain, thereby stabilizing the “closed clamshell” conformation of these two large domains in the inactive state.  Mutation to cysteine is predicted to disrupt this interaction, thereby loosening the clamshell and allowing faster GDP/GTP exchange and/or disrupting contacts between the helical domain and GAP proteins.  S211 is located in the switch II region of Gα11 and contacts the β-subunit; the mutation to tryptophan disrupts binding to the β-subunit, which is predicted to enhance agonist-dependent signaling. So far, germline mutations in Gα11 have not been described in humans.  It is also remarkable that the heterozygous germline mutations found in our IHP families only result in changes in mineral ion homeostasis.

Nothing to Disclose: MM, MH, BB, SC, KD, DL, EL, MD, SG, HWJ

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: NIH grants K08DK081669-01(MM); R37DK46718-20 and PO1- DK11794 (subproject IV) (HJ); X01 HG006062-01 (HJ and MM)