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

2016 ◽  
Vol 31 (6) ◽  
pp. 1200-1206 ◽  
Author(s):  
Caroline M Gorvin ◽  
Treena Cranston ◽  
Fadil M Hannan ◽  
Nigel Rust ◽  
Asjid Qureshi ◽  
...  
Keyword(s):  
G Protein ◽  
Familial Hypocalciuric Hypercalcemia ◽  
Loss Of Function ◽  
Protein Subunit

scholarly journals Cinacalcet Rectifies Hypercalcemia in a Patient With Familial Hypocalciuric Hypercalcemia Type 2 (FHH2) Caused by a Germline Loss-of-Function Gα11 Mutation

2017 ◽  
Vol 33 (1) ◽  
pp. 32-41 ◽  
Author(s):  
Caroline M Gorvin ◽  
Fadil M Hannan ◽  
Treena Cranston ◽  
Helena Valta ◽  
Outi Makitie ◽  
...  
Keyword(s):  
Familial Hypocalciuric Hypercalcemia ◽  
Loss Of Function

scholarly journals Disorders of the calcium-sensing receptor and partner proteins: insights into the molecular basis of calcium homeostasis

2016 ◽  
Vol 57 (3) ◽  
pp. R127-R142 ◽  
Author(s):  
Fadil M Hannan ◽  
Valerie N Babinsky ◽  
Rajesh V Thakker
Keyword(s):  
G Protein ◽  
Hormone Secretion ◽  
Urinary Calcium ◽  
Calcium Excretion ◽  
Loss Of Function ◽  
Mineral Density ◽  
Gain Of Function ◽  
Type 3

The extracellular calcium (Ca2+o)-sensing receptor (CaSR) is a family C G protein-coupled receptor, which detects alterations in Ca2+o concentrations and modulates parathyroid hormone secretion and urinary calcium excretion. The central role of the CaSR in Ca2+o homeostasis has been highlighted by the identification of mutations affecting the CASR gene on chromosome 3q21.1. Loss-of-function CASR mutations cause familial hypocalciuric hypercalcaemia (FHH), whereas gain-of-function mutations lead to autosomal dominant hypocalcaemia (ADH). However, CASR mutations are only detected in ≤70% of FHH and ADH cases, referred to as FHH type 1 and ADH type 1, respectively, and studies in other FHH and ADH kindreds have revealed these disorders to be genetically heterogeneous. Thus, loss- and gain-of-function mutations of the GNA11 gene on chromosome 19p13.3, which encodes the G-protein α-11 (Gα11) subunit, lead to FHH type 2 and ADH type 2, respectively; whilst loss-of-function mutations of AP2S1 on chromosome 19q13.3, which encodes the adaptor-related protein complex 2 sigma (AP2σ) subunit, cause FHH type 3. These studies have demonstrated Gα11 to be a key mediator of downstream CaSR signal transduction, and also revealed a role for AP2σ, which is involved in clathrin-mediated endocytosis, in CaSR signalling and trafficking. Moreover, FHH type 3 has been demonstrated to represent a more severe FHH variant that may lead to symptomatic hypercalcaemia, low bone mineral density and cognitive dysfunction. In addition, calcimimetic and calcilytic drugs, which are positive and negative CaSR allosteric modulators, respectively, have been shown to be of potential benefit for these FHH and ADH disorders.

scholarly journals Autosomal Dominant Hypocalcemia Due to a GNA11 Variant: The First Case in Japan

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A183-A183
Author(s):  
Ichiro Yamauchi ◽  
Yohei Ueda ◽  
Taku Sugawa ◽  
Takuro Hakata ◽  
Haruka Fujita ◽  
...  
Keyword(s):  
G Protein ◽  
Serum Calcium Level ◽  
Autosomal Dominant ◽  
Serum Phosphate ◽  
Serum Phosphate Level ◽  
Protein Subunit ◽  
Gain Of Function ◽  
Gene Coding ◽  
Autosomal Dominant Hypocalcemia

Abstract Background: Autosomal dominant hypocalcemia (ADH) is characterized by hypocalcemia and hyperphosphatemia due to hypoparathyroidism. ADH type 1 is caused by gain-of-function variants in CASR gene coding the calcium-sensing receptor. Recently, ADH type 2 caused by gain-of-function variants in GNA11 gene coding G-protein subunit α11 has been recognized. Case: A 32-year-old female patient visited our hospital because she suffered from hyperhidrosis, exertional dyspnea, and palpitations. She had a past medical history of paroxysmal kinesigenic dyskinesia confirmed by genetic analysis of PRRT2. Although her sister has unspecified epilepsy, no members of her kindred have episodes of tetany. Her height was 155.7 cm and weight was 64.1 kg. She had goiter with tremor and tachycardia and was diagnosed as Graves’ disease (fT3 >32.55 pg/mL, fT4 >7.77 ng/dL, TSH <0.005 µIU/mL, and TRAb 36.9 IU/L). Thiamazole therapy ameliorated her hyperthyroidism, while serum calcium level was low (7.5 mg/dL) and serum phosphate level was slight high (5.1 mg/dL). Hypoparathyroidism was confirmed because intact-PTH was relatively low (20 pg/mL) under the hypocalcemia. Her episode of tetany that she could not sit on her heels from childhood and her basal ganglia calcification in head CT scan suggest the long disease duration. Germline whole exome sequence detected a rare variant in GNA11 gene; c.1023C>A resulted in p.Phe341Leu. There were no relevant pathogenic variants in other candidate genes such as CASR, PTH, and GCM2. Treatment with 2 µg/day of alfacalcidol and 1200 mg/day of calcium aspartate could not normalize serum calcium level (7.0 mg/dL) and serum phosphate level (5.3 mg/dL) even after 1 year. Conclusions: The pathogenicity of the variant, p.Phe341Leu, in GNA11 gene was previously confirmed [1]. ADH type 2 is extremely rare as our literature review found only four previous reports; 17 patients in 5 families [1–4]. Phenotypes of the present case are mild and skeletal growth is normal. Meanwhile, we are having difficulty in management of her hypocalcemia, even though Graves’ disease might affect her bone metabolism. Optimal therapy for ADH type 2 needs further investigation. References: [1] Nesbit et al. Mutations Affecting G-protein Subunit α11 in Hypercalcemia and Hypocalcemia. N Engl J Med. 2013; 368: 2476–2486. [2] Li et al. Autosomal Dominant Hypoparathyroidism Caused by Germline Mutation in GNA11: Phenotypic and Molecular Characterization. J Clin Endocrinol Metab. 2014; 99: 1774–83. [3] Piret et al. Identification of a G-Protein Subunit-α11 Gain-of-Function Mutation, Val340Met, in a Family With Autosomal Dominant Hypocalcemia Type 2 (ADH2). J Bone Miner Res. 2016; 31: 1207–14. [4] Tenhola et al. Impaired Growth and Intracranial Calcifications in Autosomal Dominant Hypocalcemia Caused by a GNA11 Mutation. Eur J Endocrinol. 2016; 175: 211–8.

scholarly journals Endocrine regulation of G-protein subunit production in an animal model of type 2 diabetes mellitus

2001 ◽  
Vol 168 (3) ◽  
pp. 509-515 ◽  
Author(s):  
BD Rodgers ◽  
M Bernier ◽  
MA Levine
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Animal Model ◽  
Type 2 Diabetes Mellitus ◽  
Animal Models ◽  
G Protein ◽  
Dependent Manner ◽  
Protein Subunit

Adipocyte beta-adrenergic sensitivity is compromised in animal models of obesity and type 2 diabetes. Although changes in the membrane concentrations of G-protein alpha subunits (Galpha) have been implicated, it remains to be determined how these changes are affected by insulin resistance in the different animal models. Because previous studies used young animals, we measured the concentrations of Galpha and Gbeta subunits in epididymal fat from aged (48 weeks old) db/db mice and from their lean littermates to more closely reproduce the model of type 2 diabetes mellitus. Levels of immunoreactive Galphas, Galphai(1/2), Galphao and Galphaq/11 were all significantly greater in adipocyte membranes from the db/db mice than in membranes from their lean non-diabetic littermate controls. Levels of Galphai(1) and Galphai(2) were also individually determined and although they appeared to be slightly higher in db/db membranes, these differences were not significant. Although the levels of both Galphas isoforms were elevated, levels of the 42 and 46 kDa proteins rose by approximately 42% and 20% respectively, indicating differential protein processing of Galphas. By contrast, levels of Galphai3 were similar in the two groups. The levels of common Gbeta and Gbeta2 were also elevated in db/db mice, whereas Gbeta1 and Gbeta4 levels were not different. To determine whether these changes were due to insulin resistance per se or to elevated glucocorticoid production, G-protein subunit levels were quantified in whole cell lysates from 3T3-L1 adipocytes that were stimulated with different concentrations of either insulin or corticosterone. Although none of the subunit levels was affected by insulin, the levels of both Galphas isoforms were increased equally by corticosterone in a concentration-dependent manner. Since glucocorticoids are known regulators of Galphas gene expression in many cell types and in adipocytes from diabetic rodents, the results presented herein appear to more accurately reflect diabetic pathophysiology than do those of previous studies which report a decrease in Galphas levels. Taken together, these results indicate that most of the selective changes in G-protein subunit production in adipocytes from this animal model of type 2 diabetes may not be due to diminished insulin sensitivity, but may be due to other endocrine or metabolic abnormalities associated with the diabetic phenotype.

scholarly journals Role of Two G-Protein Alpha Subunits, TgaA and TgaB, in the Antagonism of Plant Pathogens by Trichoderma virens

2004 ◽  
Vol 70 (1) ◽  
pp. 542-549 ◽  
Author(s):  
Prasun K. Mukherjee ◽  
Jagannathan Latha ◽  
Ruthi Hadar ◽  
Benjamin A. Horwitz
Keyword(s):  
G Protein ◽  
Plant Pathogens ◽  
Sclerotium Rolfsii ◽  
Trichoderma Virens ◽  
Loss Of Function ◽  
Wild Type ◽  
Protein Subunit ◽  
Α Subunit ◽  
Germ Tubes

ABSTRACT G-protein α subunits are involved in transmission of signals for development, pathogenicity, and secondary metabolism in plant pathogenic and saprophytic fungi. We cloned two G-protein α subunit genes, tgaA and tgaB, from the biocontrol fungus Trichoderma virens. tgaA belongs to the fungal Gαi class, while tgaB belongs to the class defined by gna-2 of Neurospora crassa. We compared loss-of-function mutants of tgaA and tgaB with the wild type for radial growth, conidiation, germination of conidia, the ability to overgrow colonies of Rhizoctonia solani and Sclerotium rolfsii in confrontation assays, and the ability to colonize the sclerotia of these pathogens in soil. Both mutants grew as well as the wild type, sporulated normally, did not sporulate in the dark, and responded to blue light by forming a conidial ring. The tgaA mutants germinated by straight unbranched germ tubes, while tgaB mutants, like the wild type, germinated by wavy and highly branched germ tubes. In confrontation assays, both tgaA and tgaB mutants and the wild type overgrew, coiled, and lysed the mycelia of R. solani, but tgaA mutants had reduced ability to colonize S. rolfsii colonies. In the soil plate assay, both mutants parasitized the sclerotia of R. solani, but tgaA mutants were unable to parasitize the sclerotia of S. rolfsii. Thus, tgaA is involved in antagonism against S. rolfsii, but neither G protein subunit is involved in antagonism against R. solani. T. virens, which has a wide host range, thus employs a G-protein pathway in a host-specific manner.

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

2016 ◽  
Vol 31 (6) ◽  
pp. 1207-1214 ◽  
Author(s):  
Sian E Piret ◽  
Caroline M Gorvin ◽  
Alistair T Pagnamenta ◽  
Sarah A Howles ◽  
Treena Cranston ◽  
...  
Keyword(s):  
G Protein ◽  
Autosomal Dominant ◽  
Protein Subunit ◽  
Gain Of Function ◽  
Autosomal Dominant Hypocalcemia

GNA11 loss-of-function mutations cause familial hypocalciuric hypercalcaemia type 2 (FHH2)

2013 ◽  
pp. 1-1
Author(s):  
Fadil Hannan ◽  
M A Nesbit ◽  
Sarah Howles ◽  
Valerie Babinsky ◽  
Treena Cranston ◽  
...  
Keyword(s):  
Loss Of Function

The calcilytic NPS2143 rectifies the gain-of-function associated with G-protein [alpha] 11 mutations causing autosomal dominant hypocalcaemia type 2

2014 ◽  
Author(s):  
Valerie Babinsky ◽  
Fadil Hannan ◽  
M Andrew Nesbit ◽  
Sarah Howles ◽  
Jianxin Hu ◽  
...  
Keyword(s):  
G Protein ◽  
Autosomal Dominant ◽  
Gain Of Function
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