Targeted long-read sequencing reveals allele-specific methylation profiles at the GNAS locus in pseudohypoparathyroidism with various etiologies

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ID: 333811
2026
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Abstract
Abstract Patients with pseudohypoparathyroidism (PHP) show parathyroid hormone resistance due to reduced Gsα expression. Loss-of-function variants in maternal Gsα-coding exons cause PHP type 1A (PHP1A), and methylation defects in GNAS-differentially methylated regions (DMRs) at the GNAS locus cause PHP type 1B (PHP1B). The GNAS-AS1:TSS-DMR (AS1-DMR), GNAS-AS2:TSS-DMR (AS2-DMR), GNAS-XL:Ex1-DMR (XL-DMR), and GNAS-A/B:TSS-DMR (A/B-DMR) are maternally methylated. The GNAS-NESP:TSS-DMR (NESP-DMR) is paternally methylated. STX16 functions as a long-range enhancer for NESP55 and XL. PHP1B cases commonly exhibit hypomethylated A/B-DMR and various methylation patterns in other GNAS-DMRs; however, the regulatory mechanisms for methylation patterns in GNAS-DMRs remain unclear. We evaluated allele-specific methylation levels for all CpGs within the GNAS locus together with structural abnormalities using targeted long-read sequencing (T-LRS) in a PHP1A case with a deletion affecting the 3′ side A/B-DMR to GNAS exon 1, eight PHP1B cases (three familial cases [maternal STX16 deletion, maternal GNAS duplication, and retrotransposon insertion on the maternal allele], a sporadic case with STX16 deletion, and four epimutation cases [two typical and two atypical methylation patterns]), and an individual with paternal GNAS duplication showing normal phenotype. The PHP1A case showed normal methylation at the intact A/B-DMR, narrowing the critical region for the establishment and/or maintenance of the maternal methylation imprint in the A/B-DMR. The case with STX16 deletion and the case with maternal duplication causing elongation of the distance between STX16 and the AS2-DMR showed hypomethylated AS2-DMR, suggesting the incomplete enhancer effect of STX16 on the AS2-DMR. Furthermore, we detected the precise region of the AS2-DMR. The case with retrotransposon insertion (chr20:58,863,683) showed markedly hypomethylated A/B-DMR, plus mild hypomethylation of the AS1-DMR, AS2-DMR, and XL-DMR, undetected by conventional methylation analyses. Sporadic cases exhibited mosaic methylation abnormalities in all GNAS-DMRs, indicating that abnormal methylation occurred during early embryogenesis. T-LRS is a powerful tool for clarifying methylation pattern regulation in GNAS-DMRs. (300/300)
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Authors Sayuri Nakamura, Hiromune Narusawa, Tatsuki Urakawa, Yukie Nakagawa, Kyoichiro Tsuchiya, Taro Shimamoto, Takahiro Mochizuki, Jun Mori, Kensuke Shoji, Sayaka Kawashima, Michiko Okajima, Akiko Yuno, Hirotaka Komaba, Akie Nakamura, Maki Fukami, Masayo Kagami
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/zjag150
URL
https://doi.org/10.1093/jbmr/zjag150
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