Autosomal dominant pseudohypoparathyroidism type Ib is associated with a heterozygous microdeletion that likely disrupts a putative imprinting control element of GNAS
Murat Bastepe, … , John D. Crawford, Harald Jüppner
Murat Bastepe, … , John D. Crawford, Harald Jüppner
Published October 15, 2003
Citation Information: J Clin Invest. 2003;112(8):1255-1263. https://doi.org/10.1172/JCI19159.
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Article Genetics

Autosomal dominant pseudohypoparathyroidism type Ib is associated with a heterozygous microdeletion that likely disrupts a putative imprinting control element of GNAS

Abstract

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.

Authors

Murat Bastepe, Leopold F. Fröhlich, Geoffrey N. Hendy, Olafur S. Indridason, Robert G. Josse, Hiroyuki Koshiyama, Jarmo Körkkö, Jon M. Nakamoto, Arlan L. Rosenbloom, Arnold H. Slyper, Toshitsugu Sugimoto, Agathocles Tsatsoulis, John D. Crawford, Harald Jüppner

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Possible molecular mechanism underlying the marked loss of Gsα expressio...
Possible molecular mechanism underlying the marked loss of Gsα expression in the renal proximal tubule in AD-PHP-Ib. Maternal inheritance of the microdeletion is associated with loss of methylation at exon A/B and no epigenetic abnormalities at the NESP55 and XL DMRs, while paternal inheritance of the same deletion is not associated with methylation defects. We thus postulate that the identified microdeletion, which includes STX16 exons 4–6, disrupts a putative cis-acting element regulating the exon A/B methylation imprint. It has been suggested that in the renal proximal tubules, a lack of exon A/B methylation and/or active transcription of A/B mRNA, both of which are normally seen on the paternal GNAS allele, mediate, in cis, the silencing of Gsα transcription (24). Therefore, the maternal loss of exon A/B methylation in AD-PHP-Ib is predicted to cause a marked reduction in Gsα expression levels in that tissue, thereby leading to resistance to PTH (and perhaps to other hormones), whose action is mediated by the PTH/PTHrP receptor, a predominantly Gsα-coupled receptor (43). Black and gray boxes depict exons of STX16 and GNAS in the sense or antisense direction, respectively. White boxes, NPEPL1; asterisks, CpG methylation; arrows, direction of active transcription.