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

Yuno, Akiko; Usui, Takeshi; Yambe, Yuko; Higashi, Kiichiro; Ugi, Satoshi; Shinoda, Junji; Mashio, Yasuo; Shimatsu, Akira

doi:10.1530/eje-12-0548

Cited by 13 publications

(16 citation statements)

References 35 publications

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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%

“…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%

“…Unassisted and uneventful pregnancies have been reported in female patients with PHP1A 120,221 and autosomal dominant PHP1B 44,72,153,160,216 ; these pregnancies are more often seen in women with PPHP, who give birth to offspring with PHP1A 24,36,45,117,122,[221][222][223] . In a few cases, either infertility 193 or the need for the use of an assisted reproductive technique to obtain pregnancy 47,224,225 have been reported.…”

Section: Alterations In Gonadal Functionmentioning

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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Section: Molecular Diagnosismentioning

confidence: 92%

Section: Molecular Diagnosismentioning

confidence: 97%

Section: Genetic Counsellingmentioning

confidence: 99%

Section: Management Of Tsh Resistancementioning

confidence: 99%

Section: Alterations In Gonadal Functionmentioning

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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Pseudohypoparathyroidism

Linglart¹,

Levine²,

Jüppner³

2018

Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism

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Preferential Maternal Transmission of STX16-GNAS Mutations Responsible for Autosomal Dominant Pseudohypoparathyroidism Type Ib (PHP1B): Another Example of Transmission Ratio Distortion

Kiuchi

Reyes

Jüppner

2020

Journal of Bone and Mineral Research

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Preferential transmission of a genetic mutation to the next generation, referred to as transmission ratio distortion (TRD), is well established for several dominant disorders, but underlying mechanisms remain undefined. Recently, TRD was reported for patients affected by pseudohypoparathyroidism type Ia or pseudopseudohypoparathyroidism. To determine whether TRD is observed also for autosomal dominant pseudohypoparathyroidism type Ib (AD‐PHP1B), we analyzed kindreds with the frequent 3‐kb STX16 deletion or other STX16/GNAS mutations. If inherited from a female, these genetic defects lead to loss‐of‐methylation at exon A/B alone or at all three differentially methylated regions (DMR), resulting in parathyroid hormone (PTH)‐resistant hypocalcemia and hyperphosphatemia and possibly resistance to other hormones. In total, we investigated 212 children born to 80 females who are unaffected carriers of a STX16/GNAS mutation (n = 47) or affected by PHP1B (n = 33). Of these offspring, 134 (63.2%) had inherited the genetic defect (p = .00012). TRD was indistinguishable for mothers with a STX16/GNAS mutation on their paternal (unaffected carriers) or maternal allele (affected). The mechanisms favoring transmission of the mutant allele remain undefined but are likely to include abnormalities in oocyte maturation. Search for mutations in available descendants of males revealed marginally significant evidence for TRD (p = .038), but these analyses are less reliable because many more offspring of males than females with a STX16/GNAS mutation were lost to follow‐up (31 of 98 versus 6 of 218). This difference in follow‐up is probably related to the fact that inheritance of a mutation from a male does not have clinical implications, whereas inheritance from an affected or unaffected female results in PHP1B. Lastly, affected PHP1B females had fewer descendants than unaffected carriers, but it remains unclear whether abnormal oocyte development or impaired actions of reproductive hormones are responsible. Our findings highlight previously not recognized aspects of AD‐PHP1B that are likely to have implications for genetic testing and counseling. © 2020 American Society for Bone and Mineral Research (ASBMR).

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

Cited by 13 publications

References 35 publications

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

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

Pseudohypoparathyroidism

Preferential Maternal Transmission of STX16-GNAS Mutations Responsible for Autosomal Dominant Pseudohypoparathyroidism Type Ib (PHP1B): Another Example of Transmission Ratio Distortion

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