Pseudohypoparathyroidism and<i>GNAS</i>Epigenetic Defects: Clinical Evaluation of Albright Hereditary Osteodystrophy and Molecular Analysis in 40 Patients

Mantovani, Giovanna; Sanctis, Luisa De; Barbieri, Anna Maria; Elli, Francesca Marta; Bollati, Valentina; Vaira, Valentina; Labarile, Pamela; Bondioni, Sara; Peverelli, Erika; Lania, Andrea; Beck‐Peccoz, Paolo; Spada, Anna

doi:10.1210/jc.2009-0176

Cited by 146 publications

(121 citation statements)

References 30 publications

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“…In a subset of patients with PHP1A and varying degree of AHO, LOI of GNAS identical to that of PHP1B has been reported, suggesting a molecular and clinical overlap between the two subtypes (71), further confirmed (72,73,74,75). 2.…”

Section: Challenges and Limitations Of The Current Classificationmentioning

confidence: 79%

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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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131

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: 79%

“…Growth hormone deficiency and premature closure of the epiphysis result in short stature (16,82,97,105). Growth retardation has also been observed in PHP1B, although only in exceptional cases (71,74), and in patients with Eiken dysplasia (10).…”

Section: Intrauterine and Postnatal Growth Retardationmentioning

confidence: 99%

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

Self Cite

131

124

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“…Recent data showed that GNAS-related disorders are more heterogeneous than previously understood. Molecular overlap between clinically diagnosed PHP-Ia and -Ib has been reported (29,30,31,32). In addition to sequencing analysis of GNAS, MS-MLPA is a powerful tool for molecular diagnosis in individual patients and provides fruitful information that will lead to a better understanding of these disorders by revealing various genetic and/or epigenetic alterations in each clinical case.…”

Section: Discussionmentioning

confidence: 99%

Genetic and epigenetic states of the GNAS complex in pseudohypoparathyroidism type Ib using methylation-specific multiplex ligation-dependent probe amplification assay

Yuno

Usui

Yambe

et al. 2013

European Journal of Endocrinology

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Context: Pseudohypoparathyroidism type Ib (PHP-Ib) is a rare disorder resulting from genetic and epigenetic aberrations in the GNAS complex. PHP-Ib, usually defined by renal resistance to parathyroid hormone, is due to a maternal loss of GNAS exon A/B methylation and leads to decreased expression of the stimulatory G protein a (Gsa) in specific tissues. Objective: To clarify the usefulness of methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA), we evaluated genetic and epigenetic changes of the GNAS locus in Japanese PHP-Ib patients. Design: Retrospective case series. Patients: We studied 13 subjects with PHP-Ib (three families with eight affected members and one unaffected member and four sporadic cases). Measurements: The methylation status of GNAS differentially methylated regions (DMRs) was evaluated using MS-MLPA. The main outcome measure was the presence of deletion mutations in the GNAS locus and STX16, which were assessed using MLPA. Results: In all familial PHP-Ib cases, a w3 kb deletion of STX16 and demethylation of the A/B domain were identified. In contrast, no deletion was detected throughout the entire GNAS locus region in the sporadic cases. Broad methylation abnormalities were observed in the GNAS DMRs. Conclusions: MS-MLPA allows for precise and rapid analysis of the methylation status in GNAS DMRs as well as the detection of microdeletion mutations in PHP-Ib. Results confirm the previous findings in this disorder and demonstrate that this method is valuable for the genetic evaluation and visualizing the methylation status. The MS-MLPA assay is a useful tool that may facilitate making the molecular diagnosis of PHP-Ib.

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“…Mantovani reported that 24 of 40 patients with AHO and without mutations in Gsα coding regions showed a methylation defect in the A/B region [9]. In those patients, 6 patients showed all the 6 AHO symptoms and no correlation was observed in their study between the degree of methylation defects and the severity of AHO.…”

Section: Evaluation Of Clinical Characteristicsmentioning

confidence: 98%

“…The product was electrophoresed on a 3% agarose exon A/B region had mild AHO like phenotype [9,10]. We previously reported that the adult height of male PHP-1b patient was slightly lower than average.…”

mentioning

confidence: 99%

Establishment of diagnosis by bisulfite-treated methylation-specific PCR method and analysis of clinical characteristics of pseudohypoparathyroidism type 1b

et al. 2011

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Pseudohypoparathyroidism andGNASEpigenetic Defects: Clinical Evaluation of Albright Hereditary Osteodystrophy and Molecular Analysis in 40 Patients

Cited by 146 publications

References 30 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

Genetic and epigenetic states of the GNAS complex in pseudohypoparathyroidism type Ib using methylation-specific multiplex ligation-dependent probe amplification assay

Establishment of diagnosis by bisulfite-treated methylation-specific PCR method and analysis of clinical characteristics of pseudohypoparathyroidism type 1b

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