Similar frequency of paternal uniparental disomy involving chromosome 20q (patUPD20q) in Japanese and Caucasian patients affected by sporadic pseudohypoparathyroidism type Ib (sporPHP1B)

Takatani, Rieko; Minagawa, Masahiro; Molinaro, Angelo; Reyes, Monica; Kinoshita, Kaori; Takatani, Tomozumi; Kazukawa, Itsuro; Nagatsuma, Misako; Kashimada, Kenichi; Sato, Kenichi; Matsushita, Hiroshi; Nomura, Fumio; Shimojo, Naoki; Jüppner, Harald

doi:10.1016/j.bone.2015.05.011

Cited by 45 publications

(46 citation statements)

References 46 publications

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“…Epigenetic GNAS changes were assessed by MS-MLPA and pyrosequencing of the differentially methylated region (DMR) at GNAS exon A/B was performed as previously described (12, 20). …”

Section: Methodsmentioning

confidence: 99%

“…Microsatellite markers D20S86, 907-rep2, 261P9-CA, 806M20-CA, 543J19-TTA, and D20S171 were analyzed at the Center for Human Genetic Research of the Massachusetts General Hospital, as described (12). SNPs in the STX16 / GNAS region with a frequency above 1% in the general population (dbSNP) were analyzed as described (12, 27).…”

Section: Methodsmentioning

confidence: 99%

“…Most PHP1B cases are sporadic and these patients show broad, often partial methylation abnormalities at the different DMRs within the GNAS locus (5–10). The molecular mechanisms underlying the epigenetic changes leading to sporadic PHP1B are currently unknown, except for those cases that are caused by paternal uniparental disomy involving chromosome 20q (patUPD20q) (11, 12). Most autosomal dominant forms of PHP1B (AD-PHP1B) are due to maternal deletions comprising STX16, the gene encoding syntaxin 16; these deletions are associated with complete LOM at the GNAS exon A/B alone (6, 13–15).…”

Section: Introductionmentioning

confidence: 99%

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A Large Inversion Involving GNAS Exon A/B and All Exons Encoding Gsα Is Associated With Autosomal Dominant Pseudohypoparathyroidism Type Ib (PHP1B)

Grigelioniené

Nevalainen

Reyes

et al. 2016

Journal of Bone and Mineral Research

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Pseudohypoparathyroidism type Ib (PHP1B) is characterized primarily by resistance to parathyroid hormone (PTH) and thus hypocalcemia and hyperphosphatemia, in most case without evidence for Albright Hereditary Osteodystrophy (AHO). PHP1B is associated with epigenetic changes at one or several differentially methylated regions (DMR) within GNAS, which encodes the α-subunit of the stimulatory G protein (Gsα) and splice variants thereof. Heterozygous, maternally inherited STX16 or GNAS deletions leading to isolated loss-of-methylation (LOM) at exon A/B alone or at all maternal DMRs are the cause of autosomal dominant PHP1B (AD-PHP1B). In this study, we analyzed three affected individuals, the female proband and her two sons. All three revealed isolated LOM at GNAS exon A/B, while the proband’s healthy maternal grandmother and uncle showed normal methylation at this locus. Haplotype analysis was consistent with linkage to the STX16/GNAS region, yet no deletion could be identified. Whole genome sequencing of one of the patients revealed a large heterozygous inversion (1,882,433 bp). The centromeric breakpoint of the inversion is located 7,225 bp down-stream of GNAS exon XL, but its DMR showed no methylation abnormality raising the possibility that the inversion disrupts a regulatory element required only for establishing or maintaining exon A/B methylation. Because our three patients presented phenotypes consistent with PHP1B, not PHP1A, the Gsα promoter is probably unaffected by the inversion. Our findings expand the spectrum of genetic mutations that lead to loss-of-methylation at exon A/B alone and thus biallelic expression of the transcript derived from this alternative first GNAS exon.

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“…Epigenetic GNAS changes were assessed by MS-MLPA and pyrosequencing of the differentially methylated region (DMR) at GNAS exon A/B was performed as previously described (12, 20). …”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Large Inversion Involving GNAS Exon A/B and All Exons Encoding Gsα Is Associated With Autosomal Dominant Pseudohypoparathyroidism Type Ib (PHP1B)

Grigelioniené

Nevalainen

Reyes

et al. 2016

Journal of Bone and Mineral Research

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“…They present with broad LOI at GNAS, including the GNAS A/B:TSS-DMR. The molecular basis of this broad LOI is yet to be identified, with an exception of less than 10% of the patients who are affected by paternal complete or segmental uniparental disomy (UPD) of the chromosome 20, comprising the GNAS locus (59,60,61,62,63).…”

Section: Maternally Inherited Deletions Have Been Identified Affectinmentioning

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

132

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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“…In patients with PHP1B, the degree of TSH resistance can vary with time 52,53,102,206 . The average level of TSH is 5.3 ± 4.7 mUI/l (4.8 ± 3.4 mUI/l and 5.4 ± 5.2 mUI/l in autosomal dominant PHP1B and sporadic PHP1B, respectively), ranging from 0.8 mUI/l to 50.0 mUI/l (reFs 36,44,[46][47][48][49]51,53,54,87,89,91,102,105,131,143,153,164,166,169,178,200,[206][207][208][209][210] ).…”

Section: Management Of Tsh Resistancementioning

confidence: 99%

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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Similar frequency of paternal uniparental disomy involving chromosome 20q (patUPD20q) in Japanese and Caucasian patients affected by sporadic pseudohypoparathyroidism type Ib (sporPHP1B)

Cited by 45 publications

References 46 publications

A Large Inversion Involving GNAS Exon A/B and All Exons Encoding Gsα Is Associated With Autosomal Dominant Pseudohypoparathyroidism Type Ib (PHP1B)

A Large Inversion Involving GNAS Exon A/B and All Exons Encoding Gsα Is Associated With Autosomal Dominant Pseudohypoparathyroidism Type Ib (PHP1B)

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

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

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