Analysis of Multiple Families With Single Individuals Affected by Pseudohypoparathyroidism Type Ib (PHP1B) Reveals Only One Novel Maternally Inherited <i>GNAS</i> Deletion

Takatani, Rieko; Molinaro, Angelo; Grigelioniené, Giedré; Tafaj, Olta; Watanabe, Tomoyuki; Reyes, Monica; Sharma, Amita; Singhal, Vibha; Raymond, F. Lucy; Linglart, Agnès; Jüppner, Harald

doi:10.1002/jbmr.2731

Cited by 34 publications

(55 citation statements)

References 41 publications

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“…Most of these deletions had been identified through analyses of microsatellite markers that revealed discordance between affected family members and their mothers (6, 13, 16, 17) or copy number analyses (9, 15, 20). However, our patients revealed no evidence for an allelic loss, since we observed no discordance between 131/II-1 and her two sons for the six investigated microsatellite markers (see Fig.…”

Section: Resultsmentioning

confidence: 99%

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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Section: Resultsmentioning

confidence: 99%

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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“…The resulting biochemical changes are caused in PHP1A by point mutations, deletions, or insertions involving those maternal GNAS exons that encode Gαs, while the different forms of PHP1B are associated with a loss-of-methylation (LOM) at the maternal GNAS exon A/B alone or LOM at two additional differentially methylated regions [6,24]. These epigenetic GNAS changes reduce Gαs expression from the maternal allele through unknown mechanisms thus leading to little or no production of Gαs protein from this parental allele [6].…”

Section: Discussionmentioning

confidence: 99%

Mice maintain predominantly maternal Gαs expression throughout life in brown fat tissue (BAT), but not other tissues

Tafaj

Hann

Ayturk

et al. 2017

Bone

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Themurine Gnas (human GNAS) locus gives rise to Gαs and different splice variants thereof. The Gαs promoter is not methylated thus allowing biallelic expression in most tissues. In contrast, the alternative first Gnas/GNAS exons and their promoters undergo parent specific methylation, which limits transcription to the non-methylated allele. Pseudohypoparathyroidism type Ia (PHP1A) or type Ib (PHP1B) are caused by heterozygous maternal GNAS mutations suggesting that little or no Gαs is derived in some tissues from the non-mutated paternal GNAS thereby causing hormonal resistance. Previous data had indicated that Gαs is mainly derived from the maternal Gnas allele in brown adipose tissue (BAT) of newborn mice, yet it is biallelically expressed in adult BAT. This suggested that paternal Gαs expression is regulated by an unknown factor(s) that varies considerably with age. To extend these findings, we now used a strain-specific SNP in Gnas exon 11 (rs13460569) for evaluation of parent-specific Gαs expression through the densitometric quantification of BanII-digested RT-PCR products and digital droplet PCR (ddPCR). At all investigated ages, Gαs transcripts were derived in BAT predominantly from the maternal Gnas allele, while kidney and liver showed largely biallelic Gαs expression. Only low or undetectable levels of other paternally Gnas-derived transcripts were observed, making it unlikely that these are involved in regulating paternal Gαs expression. Our findings suggest that a cis-acting factor could be implicated in reducing paternal Gαs expression in BAT and presumably in proximal renal tubules, thereby causing PTH-resistance if the maternal GNAS/Gnas allele is mutated.

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“…By contrast, patients with PHP1B show abnormal patterns of methylation in the DMRs associated with the GNAS complex locus 45,47,[86][87][88]101,143,[151][152][153][154] . A methylation defect can be classified as partial or complete and can affect one or multiple DMRs within 20q13 (reF.…”

Section: Molecular Diagnosismentioning

confidence: 92%

“…GNAS shows differential methylation at four distinct DMRs: one paternally methylated-DMR (GNAS-NESP:TSS-DMR) and three maternally methylated-DMRs (GNAS-AS1:TSS-DMR, GNAS-XL:Ex1-DMR and GNAS A/B:TSS-DMR, according to the current nomenclature 156 ). Loss of methylation at GNAS A/B:TSS-DMR is detected in all patients with PHP1B 45,47,[86][87][88]101,143,[151][152][153][154] .…”

Section: Molecular Diagnosismentioning

confidence: 97%

“…If a female carries the STX16 or NESP/AS deletion, each of her descendants has a 50% risk of inheriting the genetic defect, and if the descendant inherits the defect, he or she will present with a methylation defect affecting only GNAS A/B:TSS-DMR or the complete GNAS locus (depending on the inherited deletion) 18 . In both cases, the descendant will develop PHP1B 45,47,[86][87][88]101,143,[151][152][153][154] . Although translocations of chromosome 20 resulting in UPD(20)pat are very rare, parental karyotyping is recommended to establish the risk of recurrence.…”

Section: Genetic Counsellingmentioning

confidence: 99%

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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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Analysis of Multiple Families With Single Individuals Affected by Pseudohypoparathyroidism Type Ib (PHP1B) Reveals Only One Novel Maternally Inherited GNAS Deletion

Cited by 34 publications

References 41 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)

Mice maintain predominantly maternal Gαs expression throughout life in brown fat tissue (BAT), but not other tissues

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

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