Angelo Milioto1, Monica Reyes1, Patrick Hanna1, Zentaro Kiuchi1, Serap Turan2, Daniel Zeve3, Chhavi Agarwal4, Giedre Grigelioniene5, Ang Chen6, Veronica Mericq7, Myrto Frangos8, Svetlana Ten9, Giovanna Mantovani10,11, Isidro B Salusky12, Peter Tebben13, Harald Jüppner1,14. 1. Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. 2. Department of Pediatric Endocrinology, Marmara University School of Medicine, Istanbul, Turkey. 3. Division of Endocrinology, Boston Children's Hospital, Boston, MA, USA. 4. Pediatric Endocrinology of New York, Scarsdale, NY, USA. 5. Department of Molecular Medicine and Surgery, Karolinska Institutet, and Department of Clinical Genetics, Karolinska University Hospital Stockholm, Stockholm, Sweden. 6. Any Chen, Arizona Kidney Disease and Hypertension Center, Flagstaff, AZ, USA. 7. Institute of Maternal and Child Research (IDIMI), University of Chile, Santiago, Chile. 8. Children's Endocrine Care, St. Louis, MO, USA. 9. Consultant of Pediatric Endocrinology, Richmond University Medical Center, Staten Island, NY, USA. 10. Endocrinology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. 11. Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy. 12. Division of Nephrology, Department of Pediatrics, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, USA. 13. Department of Internal Medicine and Pediatrics, Division of Endocrinology and Metabolism, Mayo Clinic, Rochester, MN, USA. 14. Pediatric Nephrology Unit, Department of Pediatrics, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
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.
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.
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