Autosomal Dominant Hypoparathyroidism Caused by Germline Mutation in<i>GNA11</i>: Phenotypic and Molecular Characterization

Dong, Li; Opas, Evan E.; Tuluc, Florin; Metzger, Daniel L.; Hou, Cuiping; Hákonarson, Hákon; Levine, Michael A.

doi:10.1210/jc.2014-1029

Cited by 81 publications

(112 citation statements)

References 40 publications

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“…There was no significant difference in the EC 50 values between Met340 and Leu341 (Leu341 = 2.60 mM; 95% CI, 2.49 to 2.72 mM; p > 0.05). Thus, the Val340Met missense substitution represents a novel gain‐of‐function Gα 11 mutation, similar to those reported in ADH2 patients 3, 7…”

Section: Resultssupporting

confidence: 79%

“…1) on chromosome 19p13.3,3, 6, 7 and referred to as ADH type 2 (ADH2; OMIM #615361) 3. These ADH‐associated Gα 11 mutations have been demonstrated to enhance CaSR‐mediated signaling in cellular studies, consistent with a gain‐of‐function 3, 7. ADH1 patients have calcitropic phenotypes, such as hypocalcemia with inappropriately low or normal PTH concentrations and a relative hypercalciuria that is characterized by urinary calcium to creatinine ratios that are within or above the reference range,1, 8, 9 and mice with a gain‐of‐function CaSR mutation, that are representative of ADH1, have been reported to also have non‐calcitropic phenotypes such as cataracts 10.…”

Section: Introductionmentioning

confidence: 99%

“…In contrast to ADH1, the phenotypic spectrum of ADH2 has not been fully elucidated, especially because only five ADH2 probands with Gα 11 mutations (Fig. 1) have been reported to date 3, 6, 7. Thus, it remains to be established whether ADH2 patients with germline gain‐of‐function Gα 11 mutations are susceptible to hypercalciuria, particularly when treated with active vitamin D preparations, or at risk of a Bartter‐like syndrome.…”

Section: Introductionmentioning

confidence: 99%

“…The GTPase domain (encoded by exon 1, 5′ portion of exon 2, 3′ portion of exon 4 and exons 5 to 7) is connected to the helical domain (encoded by the 3′ portion of exon 2, exon 3, and 5′ portion of exon 4) by the linker 1 (L1) and linker 2 (L2) peptides. The previously reported ADH2‐causing Arg60Cys (R60C), Arg60Leu (R60L), and Arg181Gln (R181Q) mutations3, 6, 7 are located at the interface between the helical and GTPase domains and adjacent to the linker peptides. The reported ADH2‐causing Ser211Trp (S211W) mutation is located in the α2 helix of the GTPase domain;6 and the Val340Met (V340M) mutation reported by this study (shown in bold), and the previously reported Phe341Leu (F341L) mutation3 are located in the α5 helix of the GTPase domain.…”

Section: Introductionmentioning

confidence: 99%

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Identification of a G-Protein Subunit-α11 Gain-of-Function Mutation, Val340Met, in a Family With Autosomal Dominant Hypocalcemia Type 2 (ADH2)

Piret

Gorvin

Pagnamenta

et al. 2016

Journal of Bone and Mineral Research

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Autosomal dominant hypocalcemia (ADH) is characterized by hypocalcemia, inappropriately low serum parathyroid hormone concentrations and hypercalciuria. ADH is genetically heterogeneous with ADH type 1 (ADH1), the predominant form, being caused by germline gain‐of‐function mutations of the G‐protein coupled calcium‐sensing receptor (CaSR), and ADH2 caused by germline gain‐of‐function mutations of G‐protein subunit α‐11 (Gα11). To date Gα11 mutations causing ADH2 have been reported in only five probands. We investigated a multigenerational nonconsanguineous family, from Iran, with ADH and keratoconus which are not known to be associated, for causative mutations by whole‐exome sequencing in two individuals with hypoparathyroidism, of whom one also had keratoconus, followed by cosegregation analysis of variants. This identified a novel heterozygous germline Val340Met Gα11 mutation in both individuals, and this was also present in the other two relatives with hypocalcemia that were tested. Three‐dimensional modeling revealed the Val340Met mutation to likely alter the conformation of the C‐terminal α5 helix, which may affect G‐protein coupled receptor binding and G‐protein activation. In vitro functional expression of wild‐type (Val340) and mutant (Met340) Gα11 proteins in HEK293 cells stably expressing the CaSR, demonstrated that the intracellular calcium responses following stimulation with extracellular calcium, of the mutant Met340 Gα11 led to a leftward shift of the concentration‐response curve with a significantly (p < 0.0001) reduced mean half‐maximal concentration (EC50) value of 2.44 mM (95% CI, 2.31 to 2.77 mM) when compared to the wild‐type EC50 of 3.14 mM (95% CI, 3.03 to 3.26 mM), consistent with a gain‐of‐function mutation. A novel His403Gln variant in transforming growth factor, beta‐induced (TGFBI), that may be causing keratoconus was also identified, indicating likely digenic inheritance of keratoconus and ADH2 in this family. In conclusion, our identification of a novel germline gain‐of‐function Gα11 mutation, Val340Met, causing ADH2 demonstrates the importance of the Gα11 C‐terminal region for G‐protein function and CaSR signal transduction. © 2016 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR).

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Section: Resultssupporting

confidence: 79%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Identification of a G-Protein Subunit-α11 Gain-of-Function Mutation, Val340Met, in a Family With Autosomal Dominant Hypocalcemia Type 2 (ADH2)

Piret

Gorvin

Pagnamenta

et al. 2016

Journal of Bone and Mineral Research

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“…Three‐dimensional modeling indicated the Thr54Met mutation to be located at the interdomain interface, which represents a highly conserved and critical region containing the P‐loop motif that binds GDP23, 24 and also facilitates interactions between the helical and GTPase domains that maintain Gα‐subunits in an inactive GDP‐bound conformation 22. The Thr54Met mutation likely alters GDP binding, but in contrast to the other reported Gα 11 mutations (Arg60Cys, Arg60Leu, and Arg181Gln),11, 31, 32 which are also located at the interdomain interface (Fig. 3 B, C ) and cause Gα 11 gain‐of‐function that is associated with the clinical disorder of autosomal dominant hypocalcemia type‐2 (ADH2), the Thr54Met Gα 11 mutation causes loss‐of‐function and FHH2.…”

Section: Discussionmentioning

confidence: 97%

A G-protein Subunit-α11 Loss-of-Function Mutation, Thr54Met, Causes Familial Hypocalciuric Hypercalcemia Type 2 (FHH2)

Gorvin

Cranston

Hannan

et al. 2016

Journal of Bone and Mineral Research

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Familial hypocalciuric hypercalcemia (FHH) is a genetically heterogeneous disorder with three variants, FHH1 to FHH3. FHH1 is caused by loss‐of‐function mutations of the calcium‐sensing receptor (CaSR), a G‐protein coupled receptor that predominantly signals via G‐protein subunit alpha‐11 (Gα11) to regulate calcium homeostasis. FHH2 is the result of loss‐of‐function mutations in Gα11, encoded by GNA11, and to date only two FHH2‐associated Gα11 missense mutations (Leu135Gln and Ile200del) have been reported. FHH3 is the result of loss‐of‐function mutations of the adaptor protein‐2 σ‐subunit (AP2σ), which plays a pivotal role in clathrin‐mediated endocytosis. We describe a 65‐year‐old woman who had hypercalcemia with normal circulating parathyroid hormone concentrations and hypocalciuria, features consistent with FHH, but she did not have CaSR and AP2σ mutations. Mutational analysis of the GNA11 gene was therefore undertaken, using leucocyte DNA, and this identified a novel heterozygous GNA11 mutation (c.161C>T; p.Thr54Met). The effect of the Gα11 variant was assessed by homology modeling of the related Gαq protein and by measuring the CaSR‐mediated intracellular calcium (Ca2+ i) responses of HEK293 cells, stably expressing CaSR, to alterations in extracellular calcium (Ca2+ o) using flow cytometry. Three‐dimensional modeling revealed the Thr54Met mutation to be located at the interface between the Gα11 helical and GTPase domains, and to likely impair GDP binding and interdomain interactions. Expression of wild‐type and the mutant Gα11 in HEK293 cells stably expressing CaSR demonstrate that the Ca2+ i responses after stimulation with Ca2+ o of the mutant Met54 Gα11 led to a rightward shift of the concentration‐response curve with a significantly (p < 0.01) increased mean half‐maximal concentration (EC50) value of 3.88 mM (95% confidence interval [CI] 3.76–4.01 mM), when compared with the wild‐type EC50 of 2.94 mM (95% CI 2.81–3.07 mM) consistent with a loss‐of‐function. Thus, our studies have identified a third Gα11 mutation (Thr54Met) causing FHH2 and reveal a critical role for the Gα11 interdomain interface in CaSR signaling and Ca2+ o homeostasis. © 2016 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR).

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Parathyroid Hormone

Gardella¹,

Nissenson²,

Jüppner³

2018

Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism

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Autosomal Dominant Hypoparathyroidism Caused by Germline Mutation inGNA11: Phenotypic and Molecular Characterization

Abstract: Our findings indicate that the germline gain-of-function mutation of GNA11 is a cause of ADH and implicate a novel role for GNA11 in skeletal growth.

Cited by 81 publications

References 40 publications

Identification of a G-Protein Subunit-α11 Gain-of-Function Mutation, Val340Met, in a Family With Autosomal Dominant Hypocalcemia Type 2 (ADH2)

Identification of a G-Protein Subunit-α11 Gain-of-Function Mutation, Val340Met, in a Family With Autosomal Dominant Hypocalcemia Type 2 (ADH2)

A G-protein Subunit-α11 Loss-of-Function Mutation, Thr54Met, Causes Familial Hypocalciuric Hypercalcemia Type 2 (FHH2)

Parathyroid Hormone

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