{"doi":"10.1210/clinem/dgab830","title":"Lack of <i>GNAS</i> Remethylation During Oogenesis May Be a Cause of Sporadic Pseudohypoparathyroidism Type Ib","abstract":"CONTEXT: Pseudohypoparathyroidism type Ib (PHP1B) is characterized by hypocalcemia and hyperphosphatemia due to parathyroid hormone resistance in the proximal renal tubules. Maternal pathogenic STX16/GNAS variants leading to maternal epigenetic GNAS changes impair expression of the stimulatory G protein alpha-subunit (Gsα) thereby causing autosomal dominant PHP1B. In contrast, genetic defects responsible for sporadic PHP1B (sporPHP1B) remain mostly unknown. OBJECTIVE: Determine whether PHP1B encountered after in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) causes GNAS remethylation defects similar to those in sporPHP1B. DESIGN: Retrospective analysis. RESULTS: Nine among 36 sporPHP1B patients investigated since 2000, all with loss of methylation (LOM) at the 3 maternal GNAS differentially methylated regions (DMRs) and gain of methylation at the paternal NESP DMR, had been conceived through IVF or ICSI. Besides abnormal GNAS methylation, IVF/ICSI PHP1B cases revealed no additional imprinting defects. Three of these PHP1B patients have dizygotic twins, and 4 have IVF/ICSI-conceived siblings, all with normal GNAS methylation; 2 unaffected younger siblings were conceived naturally. CONCLUSION: Sporadic and IVF/ICSI-conceived PHP1B patients revealed indistinguishable epigenetic changes at all 4 GNAS DMRs, thus suggesting a similar underlying disease mechanism. Given that remethylation at the 3 maternal DMRs occurs during oogenesis, male factors are unlikely to cause LOM postfertilization. Instead, at least some of the sporPHP1B variants could be caused by a defect or defects in an oocyte-expressed gene that is required for fertility and for re-establishing maternal GNAS methylation imprints. It remains uncertain, however, whether the lack of GNAS remethylation alone and the resulting reduction in Gsα expression is sufficient to impair oocyte maturation.","journal":"The Journal of Clinical Endocrinology & Metabolism","year":2021,"id":200619,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9602,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":389448,"name":"Monica Reyes","orcid":null,"position":1,"is_corresponding":false},{"id":492788,"name":"Patrick Hanna","orcid":"0000-0002-4998-2901","position":2,"is_corresponding":false},{"id":388249,"name":"Zentaro Kiuchi","orcid":"0000-0003-1302-7512","position":3,"is_corresponding":false},{"id":778365,"name":"Serap Turan","orcid":"0000-0002-5172-5402","position":4,"is_corresponding":false},{"id":567809,"name":"Daniel Zeve","orcid":"0000-0002-4117-1282","position":5,"is_corresponding":false},{"id":778366,"name":"Chhavi Agarwal","orcid":"0000-0002-3623-8091","position":6,"is_corresponding":false},{"id":364735,"name":"Giedré Grigelioniené","orcid":"0000-0001-9601-3137","position":7,"is_corresponding":false},{"id":778367,"name":"A. Chen","orcid":"0000-0001-9448-4306","position":8,"is_corresponding":false},{"id":394791,"name":"Verónica Mericq","orcid":"0000-0003-2287-0181","position":9,"is_corresponding":false},{"id":778907,"name":"Myrto Frangos","orcid":null,"position":10,"is_corresponding":false},{"id":778368,"name":"Svetlana Ten","orcid":"0000-0002-2565-0400","position":11,"is_corresponding":false},{"id":778369,"name":"Giovanna Mantovani","orcid":"0000-0002-9065-3886","position":12,"is_corresponding":false},{"id":339671,"name":"Isidro B. Salusky","orcid":"0000-0001-8052-416X","position":13,"is_corresponding":false},{"id":504391,"name":"Peter J. Tebben","orcid":"0000-0002-2147-0891","position":14,"is_corresponding":false},{"id":388250,"name":"Harald Jüppner","orcid":"0000-0003-1420-5683","position":15,"is_corresponding":false},{"id":778364,"name":"Angelo Milioto","orcid":"0009-0006-7768-2515","position":0,"is_corresponding":true}],"reference_count":60,"raw_metadata":null,"created_at":"2026-07-18T23:50:48.624274Z","pmid":"34791361","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}