Autosomal Dominant Pseudohypoparathyroidism Type Ib: A Novel Inherited Deletion Ablating<i>STX16</i>Causes Loss of Imprinting at the A/B DMR

Elli, Francesca Marta; Sanctis, Luisa De; Peverelli, Erika; Bordogna, Paolo; Pivetta, Barbara; Miolo, Gianmaria; Beck‐Peccoz, Paolo; Spada, Anna; Mantovani, Giovanna

doi:10.1210/jc.2013-3704

Cited by 71 publications

(70 citation statements)

References 16 publications

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“…Fifteen to twenty percent of the PHP1B cases present familial history with an autosomal dominant mode of inheritance (AD-PHP1B) through the maternal lineage. Most AD-PHP1B show loss of imprinting (LOI) limited to the GNAS A/B:TSS-DMR (more precisely a loss of methylation (LOM)) associated with deletions on the maternal allele of cis-acting control elements within STX16 or NESP55 (51,52,53,54,55), although other …”

Section: Figurementioning

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

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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: Figurementioning

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

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131

124

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“…30 Briefly, PCR amplification reactions for each amplicon consisted Figure 1 Schematic representation of GNAS locus including the genetic deletions described. Maternal STX16 deletions cause isolated A/B loss of methylation; 11,13,20,21 maternal deletion of NESP55 leads to isolated A/B loss of methylation with hemizygosity in NESP55. 22 However, maternal deletions affecting AS exons 3 and 4 result in a loss of methylation at all maternal GNAS imprints.…”

Section: Methylation Detectionmentioning

confidence: 99%

“…[16][17][18][19] On the other hand, some cases are familial with an autosomal dominant mode of inheritance (AD-PHP1B). 10 AD-PHP1B is typically associated with a loss of methylation restricted to the exon A/B DMR owing to maternally inherited microdeletions within STX16 11,13,20,21 or NESP55, 22 which likely harbour a cis-acting control element crucial for the establishment of the methylation imprint at exon A/B. In addition, deletions removing the entire NESP55 DMR as well as part of GNAS-AS transcript have also been identified in some AD-PHP1B kindreds in whom affected individuals show loss of all maternal GNAS imprints.…”

Section: Introductionmentioning

confidence: 99%

European guidance for the molecular diagnosis of pseudohypoparathyroidism not caused by point genetic variants at GNAS: an EQA study

et al. 2014

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on behalf of the EuroPHP Consortium 12Pseudohypoparathyroidism is a rare endocrine disorder that can be caused by genetic (mainly maternally inherited inactivating point mutations, although intragenic and gross deletions have rarely been reported) or epigenetic alterations at GNAS locus. Clinical and molecular characterization of this disease is not that easy because of phenotypic, biochemical and molecular overlapping features between both subtypes of the disease. The European Consortium for the study of PHP (EuroPHP) designed the present work with the intention of generating the standards of diagnostic clinical molecular (epi)genetic testing in PHP patients. With this aim, DNA samples of eight independent PHP patients carrying GNAS genetic and/or epigenetic defects (three patients with GNAS deletions, two with 20q uniparental disomy and three with a methylation defect of unknown origin) without GNAS point mutations were anonymized and sent to the five participant laboratories for their routine genetic analysis (methylation-specific (MS)-MLPA, pyrosequencing and EpiTYPER) and interpretations. All laboratories were able to detect methylation defects and, after the data analysis, the Consortium compared the results to define technical advantages and disadvantages of different techniques. To conclude, we propose as first-level investigation in PHP patients copy number and methylation analysis by MS-MLPA. Then, in patients with partial methylation defect, the result should be confirmed by single CpG bisulphite-based methods (ie pyrosequencing), whereas in case of a complete methylation defect without detectable deletion, microsatellites or SNP genotyping should be performed to exclude uniparental disomy 20.

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“…157 ). Other maternally inherited deletions and duplications have also been identified in some rare familial cases affecting either an isolated GNAS A/B:TSS-DMR 66,[158][159][160] or all four DMRs 50,159,[161][162][163] ( Supplementary Fig. 1c).…”

Section: Molecular Diagnosismentioning

confidence: 93%

Diagnosis and management of pseudohypoparathyroidism and related disorders: first international consensus statement

Mantovani¹,

Lecumberri²,

Baştepe³

et al. 2018

EJEA

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Pseu do hy popar ath yroi dism (PHP) and related disorders are associated with a spectrum of abnormal physical characteristics as well as neurocognitive and endocrine abnormalities that are caused primarily by molecular defects that impair hormonal signalling via receptors that are coupled, through the α-subunit of the stimulatory G protein (G s α), to activation of adenylyl cyclase (Fig. 1). 6,7,20,48 * Abstract | This Consensus Statement covers recommendations for the diagnosis and management of patients with pseu do hy popar ath yroi dism (PHP) and related disorders, which comprise metabolic disorders characterized by physical findings that variably include short bones, short stature, a stocky build, early-onset obesity and ectopic ossifications, as well as endocrine defects that often include resistance to parathyroid hormone (PTH) and TSH. The presentation and severity of PHP and its related disorders vary between affected individuals with considerable clinical and molecular overlap between the different types. A specific diagnosis is often delayed owing to lack of recognition of the syndrome and associated features. The participants in this Consensus Statement agreed that the diagnosis of PHP should be based on major criteria, including resistance to PTH, ectopic ossifications, brachydactyly and early-onset obesity. The clinical and laboratory diagnosis should be confirmed by a molecular genetic analysis. Patients should be screened at diagnosis and during follow-up for specific features, such as PTH resistance, TSH resistance, growth hormone deficiency , hypogonadism, skeletal deformities, oral health, weight gain, glucose intolerance or type 2 diabetes mellitus, and hypertension, as well as subcutaneous and/or deeper ectopic ossifications and neurocognitive impairment. Overall, a coordinated and multidisciplinary approach from infancy through adulthood, including a transition programme, should help us to improve the care of patients affected by these disorders.

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Autosomal Dominant Pseudohypoparathyroidism Type Ib: A Novel Inherited Deletion AblatingSTX16Causes Loss of Imprinting at the A/B DMR

Cited by 71 publications

References 16 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

European guidance for the molecular diagnosis of pseudohypoparathyroidism not caused by point genetic variants at GNAS: an EQA study

Diagnosis and management of pseudohypoparathyroidism and related disorders: first international consensus statement

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