Different Pattern of Epigenetic Changes of the<i>GNAS</i>Gene Locus in Patients With Pseudohypoparathyroidism Type Ic Confirm the Heterogeneity of Underlying Pathomechanisms in This Subgroup of Pseudohypoparathyroidism and the Demand for a New Classification of<i>GNAS</i>-Related Disorders

Brix, Bettina; Werner, Ralf; Staedt, P.; Struve, Dagmar; Hiort, Olaf; Thiele, Susanne

doi:10.1210/jc.2013-4477

Cited by 28 publications

(21 citation statements)

References 40 publications

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“…These disorders are not encompassed by the current classification system. For all these reasons, different independent studies from the authors of the present paper, as well as the 'EuroPHP network' concluded and agreed that a uniform terminology is required to create a functional working classification that reflects the current knowledge of the diseases (29,93,94).…”

Section: Challenges and Limitations Of The Current Classificationmentioning

confidence: 90%

“…Additional features that may not directly relate to AHO, yet extensively associated with PHP1A individuals, include obesity, varying degrees of intellectual disability and resistance to several hormones, including TSH, GHRH and calcitonin (23,24,25,26,27,28). The subcategory of PHP1C has all the characteristics of PHP1A, except that Gsa activity in erythrocytes was found comparable to controls (29,30).…”

Section: Figurementioning

confidence: 98%

“…Different molecular defects have been identified in patients with PHP1C, i.e. LOI at GNAS and four lossof-function mutations in the GNAS carboxyl-terminus leading to a conserved adenylyl cyclase receptorindependent activation but disrupted receptormediated activation (29,30,78).…”

Section: Challenges and Limitations Of The Current Classificationmentioning

confidence: 99%

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From pseudohypoparathyroidism to inactivating PTH/PTHrP signalling disorder (iPPSD), a novel classification proposed by the EuroPHP network

Thiele

Mantovani

Barlier

et al. 2016

European Journal of Endocrinology

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128

124

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Objective: Disorders caused by impairments in the parathyroid hormone (PTH) signalling pathway are historically classified under the term pseudohypoparathyroidism (PHP), which encompasses rare, related and highly heterogeneous diseases with demonstrated (epi)genetic causes. The actual classification is based on the presence or absence of specific clinical and biochemical signs together with an in vivo response to exogenous PTH and the results of an in vitro assay to measure Gsa protein activity. However, this classification disregards other related diseases such as acrodysostosis (ACRDYS) or progressive osseous heteroplasia (POH), as well as recent findings of clinical and genetic/epigenetic background of the different subtypes. Therefore, the EuroPHP network decided to develop a new classification that encompasses all disorders with impairments in PTH and/or PTHrP cAMP-mediated pathway. Design and methods: Extensive review of the literature was performed. Several meetings were organised to discuss about a new, more effective and accurate way to describe disorders caused by abnormalities of the PTH/PTHrP signalling pathway. Results and conclusions: After determining the major and minor criteria to be considered for the diagnosis of these disorders, we proposed to group them under the term 'inactivating PTH/PTHrP signalling disorder' (iPPSD). This terminology: (i) defines the common mechanism responsible for all diseases; (ii) does not require a confirmed genetic defect; (iii) avoids ambiguous terms like 'pseudo' and (iv) eliminates the clinical or molecular overlap

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Section: Challenges and Limitations Of The Current Classificationmentioning

confidence: 90%

Section: Figurementioning

confidence: 98%

See 1 more Smart Citation

From pseudohypoparathyroidism to inactivating PTH/PTHrP signalling disorder (iPPSD), a novel classification proposed by the EuroPHP network

Thiele

Mantovani

Barlier

et al. 2016

European Journal of Endocrinology

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128

124

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“…Although this test is not extensively used in practice, it has been effectively employed in making the precise diagnosis of the PHP subtype (see below) [34, 48). Gsα activity is measured in patient-derived erythrocytes, which are used to complement membranes from turkey erythrocytes or S49 murine lymphoma cell membranes that lack endogenous Gsα activity [49, 50].…”

Section: Genetic Disorders Resulting From Gnas Mutationsmentioning

confidence: 99%

GNAS Spectrum of Disorders

Turan

Baştepe

2015

Curr Osteoporos Rep

162

125

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The GNAS complex locus encodes the alpha-subunit of the stimulatory G protein (Gsα), a ubiquitous signaling protein mediating the actions of many hormones, neurotransmitters, and paracrine/aurocrine factors via generation of the second messenger cAMP. GNAS gives rise to other gene products, most of which exhibit exclusively monoallelic expression. In contrast, Gsα is expressed biallelically in most tissues; however, paternal Gsα expression is silenced in a small number of tissues through as-yet-poorly understood mechanisms that involve differential methylation within GNAS. Gsα-coding GNAS mutations that lead to diminished Gsα expression and/or function result in Albright’s hereditary osteodystrophy (AHO) with or without hormone resistance, i.e. pseudohypoparathyroidism type Ia/Ic and pseudo-pseudohypoparathryodism, respectively. Microdeletions that alter GNAS methylation and, thereby, diminish Gsα expression in tissues in which the paternal Gsα allele is normally silenced also cause hormone resistance, which occurs typically in the absence of AHO, a disorder termed pseudohypoparathyroidism type-Ib. Mutations of GNAS that cause constitutive Gsα signaling are found in patients with McCune-Albright syndrome, fibrous dysplasia of bone, and different endocrine and non-endocrine tumors. Clinical features of these diseases depend significantly on the parental allelic origin of the GNAS mutation, reflecting the tissue-specific paternal Gsα silencing. In this article, we review the pathogenesis and the phenotypes of these human diseases.

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“…It had previously been postulated that PHP Type Ic was due to the impairment of distinct components of the G protein-coupled receptor signalling pathway, and some individuals were shown to have mutations in exon 13 of the GNAS locus that affected receptor coupling but not cyclic AMP synthesis. However, more recent studies have shown evidence of GNAS methylation defects in this type [32] . It has been increasingly recognised that there is considerable overlap between the different subtypes of PHP Type I, as similar genetic mechanisms occur in each type.…”

Section: Pseudohypoparathyroidism Type Ic ( #612462 )mentioning

confidence: 93%

A Practical Approach to Hypocalcaemia in Children

Shaw

2015

Calcium and Bone Disorders in Children and Adolescents

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Hypocalcaemia is one of the commonest disorders of mineral metabolism seen in children and may be a consequence of several different aetiologies. These include a lack of secretion or function of parathyroid hormone, disorders of vitamin D metabolism and abnormal function of the calcium-sensing receptor. A practical approach to the investigation, diagnosis and subsequent management of hypocalcaemic disorders is presented.

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Different Pattern of Epigenetic Changes of theGNASGene Locus in Patients With Pseudohypoparathyroidism Type Ic Confirm the Heterogeneity of Underlying Pathomechanisms in This Subgroup of Pseudohypoparathyroidism and the Demand for a New Classification ofGNAS-Related Disorders

Abstract: Our results confirm that PHPIc is a heterogeneous entity caused in part by impaired Gsα function, not only due to mutations, but also due to abnormal imprinting of GNAS. However, in the majority of cases of PHPIc, the underlying etiopathogenesis remains elusive.

Cited by 28 publications

References 40 publications

From pseudohypoparathyroidism to inactivating PTH/PTHrP signalling disorder (iPPSD), a novel classification proposed by the EuroPHP network

From pseudohypoparathyroidism to inactivating PTH/PTHrP signalling disorder (iPPSD), a novel classification proposed by the EuroPHP network

GNAS Spectrum of Disorders

A Practical Approach to Hypocalcaemia in Children

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