The Experts below are selected from a list of 324 Experts worldwide ranked by ideXlab platform

Sabine Costagliola - One of the best experts on this subject based on the ideXlab platform.

  • G protein-coupled receptors: mutations and Endocrine Diseases
    Nature Reviews Endocrinology, 2011
    Co-Authors: Gilbert Vassart, Sabine Costagliola
    Abstract:

    Over the past 20 years, naturally occurring mutations that affect G protein-coupled receptors (GPCRs) have been identified, mainly in patients with Endocrine Diseases. The study of loss-of-function or gain-of-function mutations has contributed to our understanding of the pathophysiology of several Diseases with classic hypophenotypes or hyperphenotypes of the target Endocrine organs, respectively. Simultaneously, study of the mutant receptors ex vivo was instrumental in delineating the relationships between the structure and function of these important physiological and pharmacological molecules. Now that access to the crystallographic structure of a few GPCRs is available, the mechanics of these receptors can be studied at the atomic level. Progress in the fields of cell biology, molecular pharmacology and proteomics has also widened our view of GPCR functions. Initially considered simply as guanine nucleotide exchange factors capable of activating G protein-dependent regulatory cascades, GPCRs are now known to display several additional characteristics, each susceptible to alterations by disease-causing mutations. These characteristics include functionally important basal activity of the receptor; differential activation of various G proteins; differential activation of G protein-dependent and independent effects (biased agonism); interaction with proteins that modify receptor function; dimerization-dependent effects; and interaction with allosteric modulators. This Review attempts to illustrate how natural mutations of GPCR could contribute to our understanding of these novel facets of GPCR biology. G protein-coupled receptors (GPCRs) are key factors in endocrinology; studies of loss-of-function or gain-of-function mutations have contributed to our understanding of the pathophysiology of several Diseases. This Review provides an update on the field of GPCR mutations and Endocrine Diseases and illustrates how GPCR mutations might contribute to our understanding of the diverse facets of GPCRs involved in the field of endocrinology. G protein-coupled receptors (GPCRs) are the largest family of transmembrane receptors GPCRs are key factors in endocrinology, as they are the main sensors of the internal environment Hereditary and congenital forms of classic Endocrine Diseases that display hypophenotyes or hyperphenotypes of the target Endocrine organs are attributable to loss-of-function or gain-of-function mutations of GPCRs, respectively In addition to their canonical role as guanine nucleotide exchange factors, GPCRs have a series of G protein-independent effects that might be the cause of many Endocrine Diseases Endocrine phenotypes resulting from mutations that affect noncanonical functions of GPCRs remain to be identified

  • g protein coupled receptors mutations and Endocrine Diseases
    Nature Reviews Endocrinology, 2011
    Co-Authors: Gilbert Vassart, Sabine Costagliola
    Abstract:

    Over the past 20 years, naturally occurring mutations that affect G protein-coupled receptors (GPCRs) have been identified, mainly in patients with Endocrine Diseases. The study of loss-of-function or gain-of-function mutations has contributed to our understanding of the pathophysiology of several Diseases with classic hypophenotypes or hyperphenotypes of the target Endocrine organs, respectively. Simultaneously, study of the mutant receptors ex vivo was instrumental in delineating the relationships between the structure and function of these important physiological and pharmacological molecules. Now that access to the crystallographic structure of a few GPCRs is available, the mechanics of these receptors can be studied at the atomic level. Progress in the fields of cell biology, molecular pharmacology and proteomics has also widened our view of GPCR functions. Initially considered simply as guanine nucleotide exchange factors capable of activating G protein-dependent regulatory cascades, GPCRs are now known to display several additional characteristics, each susceptible to alterations by disease-causing mutations. These characteristics include functionally important basal activity of the receptor; differential activation of various G proteins; differential activation of G protein-dependent and independent effects (biased agonism); interaction with proteins that modify receptor function; dimerization-dependent effects; and interaction with allosteric modulators. This Review attempts to illustrate how natural mutations of GPCR could contribute to our understanding of these novel facets of GPCR biology.

Anna Spada - One of the best experts on this subject based on the ideXlab platform.

  • INVITED REVIEW G protein mutations in Endocrine Diseases
    2015
    Co-Authors: Andrea Lania, Giovanna Mantovani, Anna Spada
    Abstract:

    This review summarizes the pathogenetic role of naturally occurring mutations of G protein genes in Endocrine Diseases. Although in vitro mutagenesis and transfection assays indicate that several G proteins have mitogenic potential, to date only two G proteins have been identified which harbor naturally occurring mutations, Gsa, the activator of adenylyl cyclase and Gi2a, which is involved in several functions, including adenylyl cyclase inhibition and ion channel modulation. The gene encoding Gsa (GNAS1) may be altered by loss or gain of function mutations. Indeed, heterozygous inactivating germ line mutations in this gene cause pseudohypoparathyroidism type Ia, in which physical features of Albright hereditary osteodystrophy (AHO) are associated with resistance to several hormones, i.e. PTH, TSH and gonadotropins, that activate Gs-coupled receptors or pseudopseudohypoparathyroidism in which AHO is the only clinical manifestation. Evidence suggests that the variable and tissue-specific hormone resistance observed in PHP Ia may result from tissue-specific imprinting of the GNAS1 gene, although the Gsa knockout model only in part reproduces the human AHO phenotype. Activating somatic Gsa mutations leading to cell proliferation have been identified in Endocrine tumors constituted by cells in which cAMP is a mitogenic signal, i.e

  • Mechanisms of Disease: mutations of G proteins and G-protein-coupled receptors in Endocrine Diseases
    Nature Clinical Practice Endocrinology & Metabolism, 2006
    Co-Authors: Andrea Lania, Giovanna Mantovani, Anna Spada
    Abstract:

    Genes that encode G-protein-coupled receptors (GPCRs) and G proteins can have loss-of-function or gain-of-function mutations, which result in Endocrine disorders Loss-of-function mutations in GPCRs and G proteins prevent signaling in response to the corresponding agonist, and cause resistance to hormone action, which mimics hormone deficiency Gain-of-function mutations in GPCRs and G proteins lead to constitutive, agonist-independent activation of signaling, which mimics hormone excess The Diseases caused by genetic defects in GPCRs and G proteins are rare, and diagnosis requires careful clinical and biochemical work-up as well as close collaboration between clinical and molecular endocrinologists The study of the phenotypic consequences of mutations in GPCRs and G proteins has already had major implications for understanding structure–function relationships of these molecules, even if the implications for treatment of patients who carry such mutations are limited, at present Many hormones use G-protein-coupled receptors and G proteins in the target cell to transduce their signals. A range of disease-causing mutations have been characterized that mimic states of hormone deficiency or excess. This Review describes these mutations, and their resultant clinical and biochemical features. G proteins and G-protein-coupled receptors (GPCRs) mediate the effects of a number of hormones. Genes that encode these molecules are subject to loss-of function or gain-of-function mutations that result in Endocrine disorders. Loss-of-function mutations prevent signaling in response to the corresponding agonist and cause resistance to hormone actions, which mimics hormone deficiency. Gain-of-function mutations lead to constitutive, agonist-independent activation of signaling, which mimics hormone excess. Disease-causing mutations of GPCRs have been identified in patients with various disorders of the pituitary–thyroid, pituitary–gonadal and pituitary–adrenal axes, and in those with abnormalities in food intake, growth, water balance and mineral-ion turnover. The only mutational changes in G proteins unequivocally associated with Endocrine disorders occur in GNAS (guanine nucleotide-binding protein G-stimulatory subunit α, or G_sα). Heterozygous loss-of-function mutations of GNAS in the active, maternal allele cause resistance to hormones that act through G_sα-coupled GPCRs, whereas somatic gain-of-function mutations cause proliferation of Endocrine cells that recognize cyclic AMP as a mitogen. The study of mutations in G proteins and GPCRs has already had major implications for understanding the molecular basis of rare Endocrine Diseases, as well as susceptibility to multifactorial disorders that are associated with polymorphisms in these genes.

  • mechanisms of disease mutations of g proteins and g protein coupled receptors in Endocrine Diseases
    Nature Clinical Practice Endocrinology & Metabolism, 2006
    Co-Authors: Andrea Lania, Giovanna Mantovani, Anna Spada
    Abstract:

    G proteins and G-protein-coupled receptors (GPCRs) mediate the effects of a number of hormones. Genes that encode these molecules are subject to loss-of function or gain-of-function mutations that result in Endocrine disorders. Loss-of-function mutations prevent signaling in response to the corresponding agonist and cause resistance to hormone actions, which mimics hormone deficiency. Gain-of-function mutations lead to constitutive, agonist-independent activation of signaling, which mimics hormone excess. Disease-causing mutations of GPCRs have been identified in patients with various disorders of the pituitary-thyroid, pituitary-gonadal and pituitary-adrenal axes, and in those with abnormalities in food intake, growth, water balance and mineral-ion turnover. The only mutational changes in G proteins unequivocally associated with Endocrine disorders occur in GNAS (guanine nucleotide-binding protein G-stimulatory subunit alpha, or G(s)alpha). Heterozygous loss-of-function mutations of GNAS in the active, maternal allele cause resistance to hormones that act through G(s)alpha-coupled GPCRs, whereas somatic gain-of-function mutations cause proliferation of Endocrine cells that recognize cyclic AMP as a mitogen. The study of mutations in G proteins and GPCRs has already had major implications for understanding the molecular basis of rare Endocrine Diseases, as well as susceptibility to multifactorial disorders that are associated with polymorphisms in these genes.

  • g protein mutations in Endocrine Diseases
    European Journal of Endocrinology, 2001
    Co-Authors: Andrea Lania, Giovanna Mantovani, Anna Spada
    Abstract:

    This review summarizes the pathogenetic role of naturally occurring mutations of G protein genes in Endocrine Diseases. Although in vitro mutagenesis and transfection assays indicate that several G proteins have mitogenic potential, to date only two G proteins have been identified which harbor naturally occurring mutations, Gsalpha, the activator of adenylyl cyclase and Gi2alpha, which is involved in several functions, including adenylyl cyclase inhibition and ion channel modulation. The gene encoding Gsalpha (GNAS1) may be altered by loss or gain of function mutations. Indeed, heterozygous inactivating germ line mutations in this gene cause pseudohypoparathyroidism type Ia, in which physical features of Albright hereditary osteodystrophy (AHO) are associated with resistance to several hormones, i.e. PTH, TSH and gonadotropins, that activate Gs-coupled receptors or pseudopseudohypoparathyroidism in which AHO is the only clinical manifestation. Evidence suggests that the variable and tissue-specific hormone resistance observed in PHP Ia may result from tissue-specific imprinting of the GNAS1 gene, although the Gsalpha knockout model only in part reproduces the human AHO phenotype. Activating somatic Gsalpha mutations leading to cell proliferation have been identified in Endocrine tumors constituted by cells in which cAMP is a mitogenic signal, i.e. GH-secreting pituitary adenomas, hyperfunctioning thyroid adenomas and Leydig cell tumors. When the same mutations occur very early in embryogenesis they cause McCune-Albright syndrome. Although these mutations would in principle confer growth advantage, studies failed to detect differences in the clinical and hormonal phenotypes, suggesting the existence of mechanisms able to counteract the activation of the cAMP pathway. Activating mutations of Gi2alpha have been identified in a subset of ovarian, adrenal and pituitary tumors, but their prevalence and significance are still controversial. Finally, although Galpha subunits are the only components of the heterotrimeric GTP binding proteins which harbor known mutations, beta/gamma subunits should be considered possible targets of genetic alterations as suggested by the frequent presence of beta3 subunit variants in patients with essential hypertension.

  • G protein mutations in Endocrine Diseases
    'Bioscientifica', 2001
    Co-Authors: Andrea Lania, Giovanna Mantovani, Anna Spada
    Abstract:

    This review summarizes the pathogenetic role of naturally occurring mutations of G protein genes in Endocrine Diseases. Although in vitro mutagenesis and transfection assays indicate that several G proteins have mitogenic potential, to date only two G proteins have been identified which harbor naturally occurring mutations, Gs\u3b1, the activator of adenylyl cyclase and Gi2\u3b1, which is involved in several functions, including adenylyl cyclase inhibition and ion channel modulation. The gene encoding Gs\u3b1 (GNAS1) may be altered by loss or gain of function mutations. Indeed, heterozygous inactivating germ line mutations in this gene cause pseudohypoparathyroidism type Ia, in which physical features of Albright hereditary osteodystrophy (AHO) are associated with resistance to several hormones, i.e. PTH, TSH and gonadotropins, that activate Gs-coupled receptors or pseudopseudohypoparathyroidism in which AHO is the only clinical manifestation. Evidence suggests that the variable and tissue-specific hormone resistance observed in PHP Ia may result from tissue-specific imprinting of the GNAS1 gene, although the Gs\u3b1 knockout model only in part reproduces the human AHO phenotype. Activating somatic Gs\u3b1 mutations leading to cell proliferation have been identified in Endocrine tumors constituted by cells in which cAMP is a mitogenic signal, i.e. GH-secreting pituitary adenomas, hyperfunctioning thyroid adenomas and Leydig cell tumors. When the same mutations occur very early in embryogenesis they cause McCune-Albright syndrome. Although these mutations would in principle confer growth advantage, studies failed to detect differences in the clinical and hormonal phenotypes, suggesting the existence of mechanisms able to counteract the activation of the cAMP pathway. Activating mutations of Gi2\u3b1 have been identified in a subset of ovarian, adrenal and pituitary tumors, but their prevalence and significance are still controversial. Finally, although G\u3b1 subunits are the only components of the heterotrimeric GTP binding proteins which harbor known mutations, \u3b2/\u3b3 subunits should be considered possible targets of genetic alterations as suggested by the frequent presence of \u3b23 subunit variants in patients with essential hypertension

Gilbert Vassart - One of the best experts on this subject based on the ideXlab platform.

  • G protein-coupled receptors: mutations and Endocrine Diseases
    Nature Reviews Endocrinology, 2011
    Co-Authors: Gilbert Vassart, Sabine Costagliola
    Abstract:

    Over the past 20 years, naturally occurring mutations that affect G protein-coupled receptors (GPCRs) have been identified, mainly in patients with Endocrine Diseases. The study of loss-of-function or gain-of-function mutations has contributed to our understanding of the pathophysiology of several Diseases with classic hypophenotypes or hyperphenotypes of the target Endocrine organs, respectively. Simultaneously, study of the mutant receptors ex vivo was instrumental in delineating the relationships between the structure and function of these important physiological and pharmacological molecules. Now that access to the crystallographic structure of a few GPCRs is available, the mechanics of these receptors can be studied at the atomic level. Progress in the fields of cell biology, molecular pharmacology and proteomics has also widened our view of GPCR functions. Initially considered simply as guanine nucleotide exchange factors capable of activating G protein-dependent regulatory cascades, GPCRs are now known to display several additional characteristics, each susceptible to alterations by disease-causing mutations. These characteristics include functionally important basal activity of the receptor; differential activation of various G proteins; differential activation of G protein-dependent and independent effects (biased agonism); interaction with proteins that modify receptor function; dimerization-dependent effects; and interaction with allosteric modulators. This Review attempts to illustrate how natural mutations of GPCR could contribute to our understanding of these novel facets of GPCR biology. G protein-coupled receptors (GPCRs) are key factors in endocrinology; studies of loss-of-function or gain-of-function mutations have contributed to our understanding of the pathophysiology of several Diseases. This Review provides an update on the field of GPCR mutations and Endocrine Diseases and illustrates how GPCR mutations might contribute to our understanding of the diverse facets of GPCRs involved in the field of endocrinology. G protein-coupled receptors (GPCRs) are the largest family of transmembrane receptors GPCRs are key factors in endocrinology, as they are the main sensors of the internal environment Hereditary and congenital forms of classic Endocrine Diseases that display hypophenotyes or hyperphenotypes of the target Endocrine organs are attributable to loss-of-function or gain-of-function mutations of GPCRs, respectively In addition to their canonical role as guanine nucleotide exchange factors, GPCRs have a series of G protein-independent effects that might be the cause of many Endocrine Diseases Endocrine phenotypes resulting from mutations that affect noncanonical functions of GPCRs remain to be identified

  • g protein coupled receptors mutations and Endocrine Diseases
    Nature Reviews Endocrinology, 2011
    Co-Authors: Gilbert Vassart, Sabine Costagliola
    Abstract:

    Over the past 20 years, naturally occurring mutations that affect G protein-coupled receptors (GPCRs) have been identified, mainly in patients with Endocrine Diseases. The study of loss-of-function or gain-of-function mutations has contributed to our understanding of the pathophysiology of several Diseases with classic hypophenotypes or hyperphenotypes of the target Endocrine organs, respectively. Simultaneously, study of the mutant receptors ex vivo was instrumental in delineating the relationships between the structure and function of these important physiological and pharmacological molecules. Now that access to the crystallographic structure of a few GPCRs is available, the mechanics of these receptors can be studied at the atomic level. Progress in the fields of cell biology, molecular pharmacology and proteomics has also widened our view of GPCR functions. Initially considered simply as guanine nucleotide exchange factors capable of activating G protein-dependent regulatory cascades, GPCRs are now known to display several additional characteristics, each susceptible to alterations by disease-causing mutations. These characteristics include functionally important basal activity of the receptor; differential activation of various G proteins; differential activation of G protein-dependent and independent effects (biased agonism); interaction with proteins that modify receptor function; dimerization-dependent effects; and interaction with allosteric modulators. This Review attempts to illustrate how natural mutations of GPCR could contribute to our understanding of these novel facets of GPCR biology.

Andrea Lania - One of the best experts on this subject based on the ideXlab platform.

  • INVITED REVIEW G protein mutations in Endocrine Diseases
    2015
    Co-Authors: Andrea Lania, Giovanna Mantovani, Anna Spada
    Abstract:

    This review summarizes the pathogenetic role of naturally occurring mutations of G protein genes in Endocrine Diseases. Although in vitro mutagenesis and transfection assays indicate that several G proteins have mitogenic potential, to date only two G proteins have been identified which harbor naturally occurring mutations, Gsa, the activator of adenylyl cyclase and Gi2a, which is involved in several functions, including adenylyl cyclase inhibition and ion channel modulation. The gene encoding Gsa (GNAS1) may be altered by loss or gain of function mutations. Indeed, heterozygous inactivating germ line mutations in this gene cause pseudohypoparathyroidism type Ia, in which physical features of Albright hereditary osteodystrophy (AHO) are associated with resistance to several hormones, i.e. PTH, TSH and gonadotropins, that activate Gs-coupled receptors or pseudopseudohypoparathyroidism in which AHO is the only clinical manifestation. Evidence suggests that the variable and tissue-specific hormone resistance observed in PHP Ia may result from tissue-specific imprinting of the GNAS1 gene, although the Gsa knockout model only in part reproduces the human AHO phenotype. Activating somatic Gsa mutations leading to cell proliferation have been identified in Endocrine tumors constituted by cells in which cAMP is a mitogenic signal, i.e

  • Mechanisms of Disease: mutations of G proteins and G-protein-coupled receptors in Endocrine Diseases
    Nature Clinical Practice Endocrinology & Metabolism, 2006
    Co-Authors: Andrea Lania, Giovanna Mantovani, Anna Spada
    Abstract:

    Genes that encode G-protein-coupled receptors (GPCRs) and G proteins can have loss-of-function or gain-of-function mutations, which result in Endocrine disorders Loss-of-function mutations in GPCRs and G proteins prevent signaling in response to the corresponding agonist, and cause resistance to hormone action, which mimics hormone deficiency Gain-of-function mutations in GPCRs and G proteins lead to constitutive, agonist-independent activation of signaling, which mimics hormone excess The Diseases caused by genetic defects in GPCRs and G proteins are rare, and diagnosis requires careful clinical and biochemical work-up as well as close collaboration between clinical and molecular endocrinologists The study of the phenotypic consequences of mutations in GPCRs and G proteins has already had major implications for understanding structure–function relationships of these molecules, even if the implications for treatment of patients who carry such mutations are limited, at present Many hormones use G-protein-coupled receptors and G proteins in the target cell to transduce their signals. A range of disease-causing mutations have been characterized that mimic states of hormone deficiency or excess. This Review describes these mutations, and their resultant clinical and biochemical features. G proteins and G-protein-coupled receptors (GPCRs) mediate the effects of a number of hormones. Genes that encode these molecules are subject to loss-of function or gain-of-function mutations that result in Endocrine disorders. Loss-of-function mutations prevent signaling in response to the corresponding agonist and cause resistance to hormone actions, which mimics hormone deficiency. Gain-of-function mutations lead to constitutive, agonist-independent activation of signaling, which mimics hormone excess. Disease-causing mutations of GPCRs have been identified in patients with various disorders of the pituitary–thyroid, pituitary–gonadal and pituitary–adrenal axes, and in those with abnormalities in food intake, growth, water balance and mineral-ion turnover. The only mutational changes in G proteins unequivocally associated with Endocrine disorders occur in GNAS (guanine nucleotide-binding protein G-stimulatory subunit α, or G_sα). Heterozygous loss-of-function mutations of GNAS in the active, maternal allele cause resistance to hormones that act through G_sα-coupled GPCRs, whereas somatic gain-of-function mutations cause proliferation of Endocrine cells that recognize cyclic AMP as a mitogen. The study of mutations in G proteins and GPCRs has already had major implications for understanding the molecular basis of rare Endocrine Diseases, as well as susceptibility to multifactorial disorders that are associated with polymorphisms in these genes.

  • mechanisms of disease mutations of g proteins and g protein coupled receptors in Endocrine Diseases
    Nature Clinical Practice Endocrinology & Metabolism, 2006
    Co-Authors: Andrea Lania, Giovanna Mantovani, Anna Spada
    Abstract:

    G proteins and G-protein-coupled receptors (GPCRs) mediate the effects of a number of hormones. Genes that encode these molecules are subject to loss-of function or gain-of-function mutations that result in Endocrine disorders. Loss-of-function mutations prevent signaling in response to the corresponding agonist and cause resistance to hormone actions, which mimics hormone deficiency. Gain-of-function mutations lead to constitutive, agonist-independent activation of signaling, which mimics hormone excess. Disease-causing mutations of GPCRs have been identified in patients with various disorders of the pituitary-thyroid, pituitary-gonadal and pituitary-adrenal axes, and in those with abnormalities in food intake, growth, water balance and mineral-ion turnover. The only mutational changes in G proteins unequivocally associated with Endocrine disorders occur in GNAS (guanine nucleotide-binding protein G-stimulatory subunit alpha, or G(s)alpha). Heterozygous loss-of-function mutations of GNAS in the active, maternal allele cause resistance to hormones that act through G(s)alpha-coupled GPCRs, whereas somatic gain-of-function mutations cause proliferation of Endocrine cells that recognize cyclic AMP as a mitogen. The study of mutations in G proteins and GPCRs has already had major implications for understanding the molecular basis of rare Endocrine Diseases, as well as susceptibility to multifactorial disorders that are associated with polymorphisms in these genes.

  • g protein mutations in Endocrine Diseases
    European Journal of Endocrinology, 2001
    Co-Authors: Andrea Lania, Giovanna Mantovani, Anna Spada
    Abstract:

    This review summarizes the pathogenetic role of naturally occurring mutations of G protein genes in Endocrine Diseases. Although in vitro mutagenesis and transfection assays indicate that several G proteins have mitogenic potential, to date only two G proteins have been identified which harbor naturally occurring mutations, Gsalpha, the activator of adenylyl cyclase and Gi2alpha, which is involved in several functions, including adenylyl cyclase inhibition and ion channel modulation. The gene encoding Gsalpha (GNAS1) may be altered by loss or gain of function mutations. Indeed, heterozygous inactivating germ line mutations in this gene cause pseudohypoparathyroidism type Ia, in which physical features of Albright hereditary osteodystrophy (AHO) are associated with resistance to several hormones, i.e. PTH, TSH and gonadotropins, that activate Gs-coupled receptors or pseudopseudohypoparathyroidism in which AHO is the only clinical manifestation. Evidence suggests that the variable and tissue-specific hormone resistance observed in PHP Ia may result from tissue-specific imprinting of the GNAS1 gene, although the Gsalpha knockout model only in part reproduces the human AHO phenotype. Activating somatic Gsalpha mutations leading to cell proliferation have been identified in Endocrine tumors constituted by cells in which cAMP is a mitogenic signal, i.e. GH-secreting pituitary adenomas, hyperfunctioning thyroid adenomas and Leydig cell tumors. When the same mutations occur very early in embryogenesis they cause McCune-Albright syndrome. Although these mutations would in principle confer growth advantage, studies failed to detect differences in the clinical and hormonal phenotypes, suggesting the existence of mechanisms able to counteract the activation of the cAMP pathway. Activating mutations of Gi2alpha have been identified in a subset of ovarian, adrenal and pituitary tumors, but their prevalence and significance are still controversial. Finally, although Galpha subunits are the only components of the heterotrimeric GTP binding proteins which harbor known mutations, beta/gamma subunits should be considered possible targets of genetic alterations as suggested by the frequent presence of beta3 subunit variants in patients with essential hypertension.

  • G protein mutations in Endocrine Diseases
    'Bioscientifica', 2001
    Co-Authors: Andrea Lania, Giovanna Mantovani, Anna Spada
    Abstract:

    This review summarizes the pathogenetic role of naturally occurring mutations of G protein genes in Endocrine Diseases. Although in vitro mutagenesis and transfection assays indicate that several G proteins have mitogenic potential, to date only two G proteins have been identified which harbor naturally occurring mutations, Gs\u3b1, the activator of adenylyl cyclase and Gi2\u3b1, which is involved in several functions, including adenylyl cyclase inhibition and ion channel modulation. The gene encoding Gs\u3b1 (GNAS1) may be altered by loss or gain of function mutations. Indeed, heterozygous inactivating germ line mutations in this gene cause pseudohypoparathyroidism type Ia, in which physical features of Albright hereditary osteodystrophy (AHO) are associated with resistance to several hormones, i.e. PTH, TSH and gonadotropins, that activate Gs-coupled receptors or pseudopseudohypoparathyroidism in which AHO is the only clinical manifestation. Evidence suggests that the variable and tissue-specific hormone resistance observed in PHP Ia may result from tissue-specific imprinting of the GNAS1 gene, although the Gs\u3b1 knockout model only in part reproduces the human AHO phenotype. Activating somatic Gs\u3b1 mutations leading to cell proliferation have been identified in Endocrine tumors constituted by cells in which cAMP is a mitogenic signal, i.e. GH-secreting pituitary adenomas, hyperfunctioning thyroid adenomas and Leydig cell tumors. When the same mutations occur very early in embryogenesis they cause McCune-Albright syndrome. Although these mutations would in principle confer growth advantage, studies failed to detect differences in the clinical and hormonal phenotypes, suggesting the existence of mechanisms able to counteract the activation of the cAMP pathway. Activating mutations of Gi2\u3b1 have been identified in a subset of ovarian, adrenal and pituitary tumors, but their prevalence and significance are still controversial. Finally, although G\u3b1 subunits are the only components of the heterotrimeric GTP binding proteins which harbor known mutations, \u3b2/\u3b3 subunits should be considered possible targets of genetic alterations as suggested by the frequent presence of \u3b23 subunit variants in patients with essential hypertension

Claudio Tantucci - One of the best experts on this subject based on the ideXlab platform.