{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T02:25:08Z","timestamp":1785378308233,"version":"3.55.0"},"reference-count":39,"publisher":"American Society for Clinical Investigation","issue":"5","license":[{"start":{"date-parts":[[2024,3,8]],"date-time":"2024-03-08T00:00:00Z","timestamp":1709856000000},"content-version":"vor","delay-in-days":38,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["R01DK121776,R01DK046718"],"award-info":[{"award-number":["R01DK121776,R01DK046718"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,3,8]]},"abstract":"<jats:p>\n                    Pseudohypoparathyroidism type 1B (PHP1B) results from aberrant genomic imprinting at the\n                    <jats:italic>GNAS<\/jats:italic>\n                    gene. Defining the underlying genetic cause in new patients is challenging because various genetic alterations (e.g., deletions, insertions) within the\n                    <jats:italic>GNAS<\/jats:italic>\n                    genomic region, including the neighboring\n                    <jats:italic>STX16<\/jats:italic>\n                    gene, can cause PHP1B, and the genotype-epigenotype correlation has not been clearly established. Here, by analyzing patients with PHP1B with a wide variety of genotypes and epigenotypes, we identified a\n                    <jats:italic>GNAS<\/jats:italic>\n                    differentially methylated region (DMR) of distinct diagnostic value. This region,\n                    <jats:italic>GNAS<\/jats:italic>\n                    AS2, was hypomethylated in patients with genetic alterations located centromeric but not telomeric of this DMR. The AS2 methylation status was captured by a single probe of the methylation-sensitive multiplex ligation\u2013dependent probe amplification (MS-MLPA) assay utilized to diagnose PHP1B. In human embryonic stem cells, where NESP55 transcription regulates\n                    <jats:italic>GNAS<\/jats:italic>\n                    methylation status on the maternal allele, AS2 methylation depended on 2 imprinting control regions (STX16-ICR and NESP-ICR) essential for NESP55 transcription. These results suggest that the AS2 methylation status in patients with PHP1B reflects the position at which the genetic alteration affects NESP55 transcription during an early embryonic period. Therefore, AS2 methylation levels can enable mechanistic PHP1B categorization based on genotype-epigenotype correlation and, thus, help identify the underlying molecular defect in patients.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.177190","type":"journal-article","created":{"date-parts":[[2024,1,30]],"date-time":"2024-01-30T14:47:26Z","timestamp":1706626046000},"source":"Crossref","is-referenced-by-count":4,"title":["GNAS AS2 methylation status enables mechanism-based categorization of pseudohypoparathyroidism type 1B"],"prefix":"10.1172","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9787-7922","authenticated-orcid":true,"given":"Yorihiro","family":"Iwasaki","sequence":"first","affiliation":[{"name":"Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA."},{"name":"Tazuke Kofukai Medical Research Institute, Kitano Hospital, Osaka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Reyes","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harald","family":"J\u00fcppner","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA."},{"name":"Pediatric Nephrology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2643-3504","authenticated-orcid":true,"given":"Murat","family":"Bastepe","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, 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