Deletion of the NESP55 differentially methylated region causes loss of maternal GNAS imprints and pseudohypoparathyroidism type Ib

Baştepe, Murat; Fröhlich, Leopold F.; Linglart, Agnès; Abu-Zahra, Hilal; Tojo, Katsuyoshi; Ward, Leanne M.; Jüppner, Harald

doi:10.1038/ng1487

Cited by 219 publications

(199 citation statements)

References 15 publications

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“…Another study identified maternally transmitted deletions of an upstream exon of the NESP55 transcript within the GNAS locus in two families, which were associated with methylation defects at all downstream GNAS ICRs located at exons AS1, XL and A/B (Figure 2 and Table 1). 63 At least some of these deletions could affect transcription of NESP55 in oocytes, which is presumed to proceed through AS1, XL and exon A/B. In light of the study on the mouse Gnas locus, 26 it is conceivable that the absence of NESP55 transcription leads to a failure in imprint establishment.…”

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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“…22 However, maternal deletions affecting AS exons 3 and 4 result in a loss of methylation at all maternal GNAS imprints. 15,23 Gross deletions affecting some or all the DMRs of GNAS locus and leading to an apparent methylation defect has also been published. [7][8][9] EQA for PHP not caused by point genetic variants I Garin et al of 20 ng of bisulphite-treated DNA, 1 Â of Megamix Gold (Microzone Ltd, Haywards Heath, UK) and 0.2 mM of primers (Life Technologies, Carlsbad, CA, USA), and 2 ml PCR products were used as template for in vitro transcription and RNAaseA cleavage for the T-reverse reaction (Sequenom hMC, San Diego, CA, USA).…”

Section: Methylation Detectionmentioning

confidence: 99%

“…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. 15,23 However, clinical and molecular analysis for PHP is not easy to achieve because of different reasons. First, beyond the classic PHP type 1 classification, our groups and others demonstrated a genetic overlap between PHP1A and PHP1B, reporting patients with mild AHO features and methylation defects.…”

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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“…PHP-Ib patients display methylation abnormalities in the GNAS differentially methylated regions, such as NESP hypermethylation versus XL/Nespas and Exon A/B hypomethylation. 2 Familial cases of PHP-Ib present with Exon A/B-only hypomethylation 3,4 that appears to be caused by maternally inherited deletions affecting imprinting control centers in either the STX16 gene 5,6 or the NESP55/NESPAS region. 2,7 Paternal Gsalpha-inactivating mutations lead to pseudopseudohypoparathyroidism (PPHP).…”

mentioning

confidence: 99%

“…2 Familial cases of PHP-Ib present with Exon A/B-only hypomethylation 3,4 that appears to be caused by maternally inherited deletions affecting imprinting control centers in either the STX16 gene 5,6 or the NESP55/NESPAS region. 2,7 Paternal Gsalpha-inactivating mutations lead to pseudopseudohypoparathyroidism (PPHP). 1,8,9 This clinical condition is characterized by highly variable AHO features but no hormone resistance.…”

mentioning

confidence: 99%

No evidence for GNAS copy number variants in patients with features of Albright's hereditary osteodystrophy and abnormal platelet Gs activity

et al. 2012

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Albright's hereditary osteodystrophy (AHO) is characterized by short stature, round face, calcifications, obesity, brachydactyly and intellectual disability. AHO without hormone resistance is called pseudopseudohypoparathyroidism (PPHP), a rare clinical condition difficult to diagnose with highly variable features. PPHP is caused by paternally inherited loss-of-function mutations in the GNAS. Patients with 2q37 microdeletions or HDAC4 mutations are also defined as having an AHO-like phenotype with normal stimulatory G (Gs) function. We have studied 256 patients with AHO features but no other diagnosis. Their platelet Gs activity was determined via the aggregation-inhibition test showing Gs hypo-or hyperfuncton in 24% and 15% of the patients, respectively. Before initiating with detailed (epi)genetic GNAS studies, we here wanted to excluded copy number variants (CNVs) in GNAS as cause of AHO with a novel large-scale screening technique. Multiplex amplicon quantification (MAQ) for CNVs screening was developed for the 20q13.3 region including GNAS and potential long-range imprinting control elements such as STX16. This is the first large-scale GNAS CNV study in patients with common AHO features but no CNVs were detected. In conclusion, CNVs in the GNAS region are not likely to cause an AHO-like phenotype with or without abnormal platelet Gs activity. Future studies will be undertaken to find out whether these AHO patients with abnormal Gs function are characterized by GNAS coding or methylation defects.

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Deletion of the NESP55 differentially methylated region causes loss of maternal GNAS imprints and pseudohypoparathyroidism type Ib

Cited by 219 publications

References 15 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

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

No evidence for GNAS copy number variants in patients with features of Albright's hereditary osteodystrophy and abnormal platelet Gs activity

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