A Maternal Epimutation of GNAS Leads to Albright Osteodystrophy and Parathyroid Hormone Resistance

Mariot, Virginie; Maupetit‐Mehouas, Stéphanie; Sinding, Christiane; Kottler, Marie‐Laure; Linglart, Agnès

doi:10.1210/jc.2007-0927

Cited by 103 publications

(60 citation statements)

References 16 publications

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“…Recent data showed that GNAS-related disorders are more heterogeneous than previously understood. Molecular overlap between clinically diagnosed PHP-Ia and -Ib has been reported (29,30,31,32). In addition to sequencing analysis of GNAS, MS-MLPA is a powerful tool for molecular diagnosis in individual patients and provides fruitful information that will lead to a better understanding of these disorders by revealing various genetic and/or epigenetic alterations in each clinical case.…”

Section: Discussionmentioning

confidence: 99%

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

Yuno

Usui

Yambe

et al. 2013

European Journal of Endocrinology

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Context: Pseudohypoparathyroidism type Ib (PHP-Ib) is a rare disorder resulting from genetic and epigenetic aberrations in the GNAS complex. PHP-Ib, usually defined by renal resistance to parathyroid hormone, is due to a maternal loss of GNAS exon A/B methylation and leads to decreased expression of the stimulatory G protein a (Gsa) in specific tissues. Objective: To clarify the usefulness of methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA), we evaluated genetic and epigenetic changes of the GNAS locus in Japanese PHP-Ib patients. Design: Retrospective case series. Patients: We studied 13 subjects with PHP-Ib (three families with eight affected members and one unaffected member and four sporadic cases). Measurements: The methylation status of GNAS differentially methylated regions (DMRs) was evaluated using MS-MLPA. The main outcome measure was the presence of deletion mutations in the GNAS locus and STX16, which were assessed using MLPA. Results: In all familial PHP-Ib cases, a w3 kb deletion of STX16 and demethylation of the A/B domain were identified. In contrast, no deletion was detected throughout the entire GNAS locus region in the sporadic cases. Broad methylation abnormalities were observed in the GNAS DMRs. Conclusions: MS-MLPA allows for precise and rapid analysis of the methylation status in GNAS DMRs as well as the detection of microdeletion mutations in PHP-Ib. Results confirm the previous findings in this disorder and demonstrate that this method is valuable for the genetic evaluation and visualizing the methylation status. The MS-MLPA assay is a useful tool that may facilitate making the molecular diagnosis of PHP-Ib.

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Section: Discussionmentioning

confidence: 99%

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

Yuno

Usui

Yambe

et al. 2013

European Journal of Endocrinology

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“…PHP-Ia is associated with multiple hormone resistance, including toward parathyroid hormone (PTH) and thyroid stimulating hormone (TSH), and Albright hereditary osteodystrophy (AHO) (3)(4)(5)(6). Like with PHP-Ia, patients affected by PHP-Ib develop resistance toward PTH leading to hypocalcemia and hyperphosphatemia, which can sometimes be associated with mild resistance to TSH; unlike PHP-Ia, PHP-Ib appears to be only rarely associated with AHO features, such as shortening of metacarpals (13)(14)(15).…”

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confidence: 99%

Targeted deletion of the Nesp55 DMR defines another Gnas imprinting control region and provides a mouse model of autosomal dominant PHP-Ib

Fröhlich

Mrakovcic

Steinborn

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Approximately 100 genes undergo genomic imprinting. Mutations in fewer than 10 imprinted genetic loci, including GNAS, are associated with complex human diseases that differ phenotypically based on the parent transmitting the mutation. Besides the ubiquitously expressed Gsα, which is of broad biological importance, GNAS gives rise to an antisense transcript and to several Gsα variants that are transcribed from the nonmethylated parental allele. We previously identified two almost identical GNAS microdeletions extending from exon NESP55 to antisense (AS) exon 3 (delNESP55/ delAS3-4). When inherited maternally, both deletions are associated with erasure of all maternal GNAS methylation imprints and autosomal-dominant pseudohypoparathyroidism type Ib, a disorder characterized by parathyroid hormone-resistant hypocalcemia and hyperphosphatemia. As for other imprinting disorders, the mechanisms resulting in abnormal GNAS methylation are largely unknown, in part because of a paucity of suitable animal models. We now showed in mice that deletion of the region equivalent to delNESP55/delAS3-4 on the paternal allele (ΔNesp55 p ) leads to healthy animals without Gnas methylation changes. In contrast, mice carrying the deletion on the maternal allele (ΔNesp55 m ) showed loss of all maternal Gnas methylation imprints, leading in kidney to increased 1A transcription and decreased Gsα mRNA levels, and to associated hypocalcemia, hyperphosphatemia, and secondary hyperparathyroidism. Besides representing a murine autosomal-dominant pseudohypoparathyroidism type Ib model and one of only few animal models for imprinted human disorders, our findings suggest that the Nesp55 differentially methylated region is an additional principal imprinting control region, which directs Gnas methylation and thereby affects expression of all maternal Gnas-derived transcripts.genomic imprinting | Gsα | pseudohypoparathyroidism | parathyroid hormone | hormonal resistance

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“…Clinical diagnosis of PHP1A and PHP1B is hampered by (epi)genetic and clinical overlaps. [24][25][26][27] It is therefore of utmost importance to establish a reliable identification and quantification of the methylation at GNAS-DMRs to (i) provide an accurate diagnosis of PHP to patients and physicians, (ii) orientate genetic and cytogenetic investigations depending on the methylation pattern and (iii) identify patients without any known primary defect causing the methylation anomalies to nourish the research.…”

Section: Discussionmentioning

confidence: 99%

“…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. [24][25][26][27] Second, Gsa activity has also been reported to be decreased not only in patients with GNAS mutations (PHP1A) but also in patients with methylation defects at the GNAS locus. 28 Third, as mentioned above, methylation defects at the GNAS locus may be partial and undetected by non-quantitative methods of methylation analysis.…”

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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A Maternal Epimutation of GNAS Leads to Albright Osteodystrophy and Parathyroid Hormone Resistance

Cited by 103 publications

References 16 publications

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

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

Targeted deletion of the Nesp55 DMR defines another Gnas imprinting control region and provides a mouse model of autosomal dominant PHP-Ib

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

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