A GNAS1 imprinting defect in pseudohypoparathyroidism type IB

Liu, Jie; Litman, Deborah; Rosenberg, Marjorie; Yu, Shuhua; Biesecker, Leslie G.; Weinstein, Lee S.

doi:10.1172/jci10431

Cited by 273 publications

(292 citation statements)

References 40 publications

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“…[56][57][58][59] A remarkable finding with this disorder is that genetic mutations underlying the loss of methylation were initially mapped X56 kb upstream of the exon A/B ICR, indicating the presence of a longrange, cis-acting element. 56 Furthermore, heterozygous microdeletions at STX16, located approximately 220 kb upstream of the GNAS exon A/B ICR, were also found in most cases of autosomal dominant form of pseudohypoparathyroidism type Ib.…”

Section: Childhood Diseases Associated With Imprint Establishment or mentioning

confidence: 99%

Genomic imprinting and its relevance to congenital disease, infertility, molar pregnancy and induced pluripotent stem cell

Tomizawa

Sasaki

2012

J Hum Genet

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Genomic imprinting is an epigenetic gene-marking phenomenon that occurs in the germline, whereby genes are expressed from only one of the two parental copies in embryos and adults. Imprinting is essential for normal mammalian development and its disruption can cause various developmental defects and diseases. The process of imprinting in the germline involves DNA methylation of the imprint control regions (ICRs), and resulting parental-specific methylation imprints are maintained in the zygote and act as the marks controlling imprinted gene expression. Recent studies in mice have revealed new factors involved in imprint establishment during gametogenesis and maintenance during early development. Clinical studies have identified cases of imprinting disorders where involvement of factors shared by multiple ICRs for establishment or maintenance is suspected. These include Beckwith-Wiedemann syndrome, transient neonatal diabetes, Silver-Russell syndrome and others. More severe disruptions can lead to recurrent molar pregnancy, miscarriage or infertility. Imprinting defects may also occur during assisted reproductive technology or cell reprogramming. In this review, we summarize our current knowledge on the mechanisms of imprint establishment and maintenance, and discuss the relationship with various human disorders.

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Section: Childhood Diseases Associated With Imprint Establishment or mentioning

confidence: 99%

Genomic imprinting and its relevance to congenital disease, infertility, molar pregnancy and induced pluripotent stem cell

Tomizawa

Sasaki

2012

J Hum Genet

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“…Obesity is frequently associated with G protein variants [48]. GNAS1 is thought to be an imprinted gene [54,58]. While the ASIP gene encodes a paracrinesignaling molecule that causes hair follicle melanocytes to synthesize the yellow pigment, phaeomelanin, pleiotropic effects of this gene are known to include adult-onset obesity [86].…”

Section: Growth and Obesity Traitsmentioning

confidence: 99%

The evidence of associations between prion protein genotype and production, reproduction, and health traits in sheep

Sweeney

Hanrahan

2008

Vet. Res.

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“…[10][11][12][13] The postzygotic occurrence of this epigenetic defect is supported by the observation of a partial LoI in some patients. 14,15 In a small subset of these patients (10-25% according to various reports), uniparental disomy of chromosome 20q has been identified as the cause of the GNAS methylation anomaly.…”

Section: Introductionmentioning

confidence: 84%

“…PHP1B subjects display paternal-specific patterns of cytosine methylation within differentially methylated regions (DMRs) of their maternally inherited GNAS alleles, 10,11 suggesting a loss of imprinting (LoI) as the basis of the disorder.…”

Section: Introductionmentioning

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%

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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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A GNAS1 imprinting defect in pseudohypoparathyroidism type IB

Cited by 273 publications

References 40 publications

Genomic imprinting and its relevance to congenital disease, infertility, molar pregnancy and induced pluripotent stem cell

Genomic imprinting and its relevance to congenital disease, infertility, molar pregnancy and induced pluripotent stem cell

The evidence of associations between prion protein genotype and production, reproduction, and health traits in sheep

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

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