Albright Hereditary Osteodystrophy, Pseudohypoparathyroidism, and Gs Deficiency

Weinstein, Lee S.

doi:10.1007/978-1-4612-1802-9_2

Cited by 48 publications

(45 citation statements)

References 194 publications

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“…members affected with either PHP Ia or PPHP. On the contrary, no mutation in the GNAS1 coding sequence has ever been found in families in whom sporadic or familial PPHP was the only clinical manifestation (48,63,64). These results support the view that PHP Ia and isolated PPHP may represent two genetically distinct entities, even if the possibility that a defect may exist in the promoter region or in other regulatory intronic sequences of GNAS1 cannot be completely excluded.…”

Section: Albright Hereditary Osteodystrophy and Pseudohypoparathyroidismsupporting

confidence: 70%

G protein mutations in endocrine diseases

Lania

Mantovani

Spada

2001

European Journal of Endocrinology

100

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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 identi®ed 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-speci®c hormone resistance observed in PHP Ia may result from tissuespeci®c 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 identi®ed 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 Gi2a have been identi®ed in a subset of ovarian, adrenal and pituitary tumors, but their prevalence and signi®cance are still controversial. Finally, although Ga subunits are the only components of the heterotrimeric GTP binding proteins which harbor known mutations, b/g subunits should be considered possible targets of genetic alterations as suggested by the frequent presence of b3 subunit variants in patients with essential hypertension.

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Section: Albright Hereditary Osteodystrophy and Pseudohypoparathyroidismsupporting

confidence: 70%

G protein mutations in endocrine diseases

Lania

Mantovani

Spada

2001

European Journal of Endocrinology

100

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“…Characteristics include short stature, brachymetacarpia, subcutaneous ossification and developmental delay, but a remarkable feature is that presentation depends on parental origin (Davies & Hughes 1993, Wilson et al 1994. When transmitted from mothers, AHO is accompanied by the hormone resistance syndrome pseudohypoparathyroidism type 1a (PHP1a), characterised by development of end-organ resistance to a subset of hormones -parathyroid hormone, GHRH, TSH and gonadotropins -which depend on Gsa-coupled receptors (Weinstein 1998). AHO may be explained by generalised haploinsufficiency of GNAS; PHP1a represents the additional consequences of tissuespecific imprinting of GNAS -the relative silencing of the paternal allele -such that in some tissues Gsa function is effectively absent or severely reduced when the maternal allele carries a mutation.…”

Section: Imprinted Gene Disorders With a Neuroendocrine Involvementmentioning

confidence: 99%

Imprinted genes and hypothalamic function

Ivanova

Kelsey

2011

Journal of Molecular Endocrinology

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Genomic imprinting is an important and enigmatic form of gene regulation in mammals in which one copy of a gene is silenced in a manner determined by its parental history. Imprinted genes range from those with constitutive monoallelic silencing to those, typically more remote from imprinting control regions, that display developmentally regulated, tissuespecific or partial monoallelic expression. This diversity may make these genes, and the processes they control, more or less sensitive to factors that modify or disrupt epigenetic marks. Imprinted genes have important functions in development and physiology, including major endocrine/neuroendocrine axes. Owing to is central role in coordinating growth, metabolism and reproduction, as well as evidence from genetic and knockout studies, the hypothalamus may be a focus for imprinted gene action. Are there unifying principles that explain why a gene should be imprinted? Conflict between parental genomes over limiting maternal resources, but also co-adaptation between mothers and offspring, have been invoked to explain the evolution of imprinting. Recent reports suggest there may be many more genes imprinted in the hypothalamus than hitherto expected, and it will be important for these new candidates to be validated and to determine whether they conform to current notions of how imprinting is regulated. In fully evaluating the role of imprinted genes in the hypothalamus, much work needs to be done to identify the specific neuronal populations in which particular genes are expressed, establish whether there are pathways in common and whether imprinted genes are involved in long-term programming of hypothalamic functions.

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“…Genomic DNA was isolated from peripheral blood leukocytes with the phenol/chloroform method in all patients and their available parents. The 13 exons of the GNAS1 gene were amplified from one patient for each family, using 13 pairs of previously described GNAS1-specific primers (7,16). Amplification of exons 2-12 included each bordering intron region, whereas a DNA fragment from 20 bp downstream of the initiation codon to the donor site of intron 1 was amplified for exon 1 because of abundance of guanine and cytosine in the bordering regions (7).…”

Section: Subjectsmentioning

confidence: 99%

“…Type II patients show a normal cAMP urinary response, but a deficient phosphaturic response to PTH, which indicates a defect distal to cAMP generation (4,6). Three subtypes (types Ia, Ib, and Ic) are distinguished clinically and biochemically (7,8). PHP-Ia patients have a deficient G s␣ protein activity, resistance to PTH and often to other hormones (i.e.…”

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confidence: 99%

Molecular Analysis of the GNAS1 Gene for the Correct Diagnosis of Albright Hereditary Osteodystrophy and Pseudohypoparathyroidism

et al. 2003

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Pseudohypoparathyroidism (PHP) is a heterogeneous disease characterized by PTH resistance and classified as types Ia, Ib, Ic, and II, according to its different pathogenesis and phenotype. PHP-Ia patients show G s␣ protein deficiency, PTH resistance, and typical Albright hereditary osteodystrophy (AHO). Heterozygous mutations in the GNAS1 gene encoding the G s␣ protein have been identified both in PHP-Ia and in pseudopseudohypoparathyroidism (PPHP), a disorder with isolated AHO. A single GNAS1 mutation may be responsible for both PHP-Ia and PPHP in the same family when inherited from the maternal and the paternal allele, respectively, suggesting that GNAS1 is an imprinted gene. To evaluate whether molecular diagnosis is a useful tool to characterize AHO and PHP when testing for G s␣ activity and PTH resistance is not available, we have performed GNAS1 mutational analysis in 43 patients with PTH resistance and/or AHO. Sequencing of the whole coding region of the GNAS1 gene identified 11 mutations in 18 PHP patients, eight of which have not been reported previously. Inheritance was ascertained in 13 cases, all of whom had PHP-Ia: the mutated alleles were inherited from the mothers, who had AHO (PPHP), consistent with the proposed imprinting mechanism. GNAS1 molecular analysis confirmed the diagnosis of PHP-Ia and PPHP in the mutated patients. Our results stress the usefulness of this approach to obtain a complete diagnosis, expand the GNAS1 mutation spectrum, and illustrate the wide mutation heterogeneity of PHP and PHP-Ia. PHP (OMIM 103580) was the first human disease to be ascribed to deficient responsiveness to a hormone by otherwise normal target organs (1). It consists of a heterogeneous group of endocrine disorders, whose common feature is resistance to PTH, as shown by hypocalcemia, hyperphosphatemia, and elevation of serum PTH despite normal renal function (2). PTH stimulates the formation of intracellular cAMP by adenylyl cyclase through the activation of G s protein (3, 4). G s protein belongs to the superfamily of heterotrimeric G proteins formed of three subunits (␣, ␤, ␥) encoded by separate genes (5). They mediate signal transduction across cell membranes by coupling extracellular receptors to intracellular effector proteins. The activity of hormone-sensitive adenylate cyclase is regulated by at least two G proteins, one stimulatory (G s ) and one inhibitory (G i ). G protein specificity is defined by its specific ␣-subunit. G s␣ , which binds GTP and stimulates adenylyl cyclase, has GTPase activity and couples multiple receptors to the stimulation of adenylyl cyclase, including those for PTH, TSH, and LH/FSH.

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Albright Hereditary Osteodystrophy, Pseudohypoparathyroidism, and Gs Deficiency

Cited by 48 publications

References 194 publications

G protein mutations in endocrine diseases

G protein mutations in endocrine diseases

Imprinted genes and hypothalamic function

Molecular Analysis of the GNAS1 Gene for the Correct Diagnosis of Albright Hereditary Osteodystrophy and Pseudohypoparathyroidism

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