TY - JOUR AU - Bastepe, Murat AU - Fröhlich, Leopold F. AU - Hendy, Geoffrey N. AU - Indridason, Olafur S. AU - Josse, Robert G. AU - Koshiyama, Hiroyuki AU - Körkkö, Jarmo AU - Nakamoto, Jon M. AU - Rosenbloom, Arlan L. AU - Slyper, Arnold H. AU - Sugimoto, Toshitsugu AU - Tsatsoulis, Agathocles AU - Crawford, John D. AU - Jüppner, Harald T1 - Autosomal dominant pseudohypoparathyroidism type Ib is associated with a heterozygous microdeletion that likely disrupts a putative imprinting control element of GNAS PY - 2003/10/15/ AB - Patients with pseudohypoparathyroidism type Ib (PHP-Ib) have hypocalcemia and hyperphosphatemia due to renal parathyroid hormone (PTH) resistance, but lack physical features of Albright hereditary osteodystrophy. PHP-Ib is thus distinct from PHP-Ia, which is caused by mutations in the GNAS exons encoding the G protein α subunit. However, an imprinted autosomal dominant form of PHP-Ib (AD-PHP-Ib) has been mapped to a region of chromosome 20q13.3 containing GNAS. Furthermore, loss of methylation at a differentially methylated region (DMR) of this locus, exon A/B, has been observed thus far in all investigated sporadic PHP-Ib cases and the affected members of multiple AD-PHP-Ib kindreds. We now report that affected members and obligate gene carriers of 12 unrelated AD-PHP-Ib kindreds and four apparently sporadic PHP-Ib patients, but not healthy controls, have a heterozygous approximately 3-kb microdeletion located approximately 220 kb centromeric of GNAS exon A/B. The deleted region, which is flanked by two direct repeats, includes three exons of STX16, the gene encoding syntaxin-16, for which no evidence of imprinting could be found. Affected individuals carrying the microdeletion show loss of exon A/B methylation but no epigenetic abnormalities at other GNAS DMRs. We therefore postulate that this microdeletion disrupts a putative cis-acting element required for methylation at exon A/B, and that this genetic defect underlies the renal PTH resistance in AD-PHP-Ib. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI19159 VL - 112 IS - 8 UR - https://doi.org/10.1172/JCI19159 SP - 1255 EP - 1263 PB - The American Society for Clinical Investigation ER -