Session: OR43-Disorders of Calcium Homeostasis
Room 122 (Moscone Center)
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
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