Abnormal position of a GNAS methylation regulatory element causes autosomal dominant pseudohypoparathyroidism type 1B (PHP1B)

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ID: 320163
2026
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Abstract
The parental imprinted GNAS complex locus encodes the α-subunit of the stimulatory G protein. Pseudohypoparathyroidism type Ib (PHP1B) is characterized by renal resistance to parathormone and is caused by epigenetic anomalies, ie, at least the loss of methylation (LOM) at the A/B differentially methylated region (DMR). LOM or gain of methylation (GOM) may also affect other DMRs and different transcripts expressions within the locus (NESP, exon H, AS1, XLαs, A/B). Most PHP1B are sporadic and result from abnormal methylation of all DMRs in the regulatory region of GNAS. Autosomal dominant PHP1B (AD-PHP1B) is usually caused by a recurrent STX16 gene microdeletion in the maternal allele which leads to isolated LOM at the A/B DMR. In this study, we investigated an AD-PHP1B family without STX16 deletion using whole genome sequencing (WGS). The two affected siblings presented a LOM at the A/B DMR and the half telomeric portion of the XLαs DMR and their healthy mother presented a partial GOM at the AS1 DMR and the half centromeric portion of the XLαs DMR. The WGS analysis revealed a 140-kb paracentric inversion with breakpoints located in the NPEPL1 gene and XLαs DMR. We identified the first inversion involving the regulatory region of GNAS locus leading to a maternally inherited AD-PHP1B. This observation provides additional insight into the methylation regulatory elements in the GNAS locus on both alleles, especially on NESP and exon H transcription-mediated methylation. This study will help design subsequent strategies for further studies.
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Authors Andreea Apetrei, Nicolas Richard, Yorihiro Iwasaki, Harald Jüppner, Magali Demoor, Nicolas Gruchy, Hélène Bony, Rachel Desailloud, Arnaud Molin
Journal journal of bone and mineral research : the official journal of the american society for bone and mineral research
Year 2026
DOI
10.1093/jbmr/zjag107
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