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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Figure 1

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The GNAS locus and parent-of-origin–specific inheritance of hormone resi...
The GNAS locus and parent-of-origin–specific inheritance of hormone resistance. (a) GNAS gives rise, besides Gsα, to multiple other transcripts including NESP55, XLαs, the antisense (AS) and A/B (also referred to as 1A or 1′), all of which show differential methylation (asterisks) in their promoters and are expressed exclusively from the non-methylated paternal (p) or maternal (m) allele. Exons that lead to transcripts in the sense (right-pointing arrow) and antisense (left-pointing arrow) directions are depicted as black and gray boxes, respectively, and the splice patterns are indicated. Note that the promoter giving rise to the Gsα transcript, encoded by exons 1 through 13, does not show differential methylation. However, although expression is biallelic in most tissues, Gsα transcription from the paternal GNAS allele is proposed to be silenced in a limited number of cells (dotted arrow), including those in renal proximal tubules. (b) In kindreds with PHP-Ia and PPHP, as well as in those with AD-PHP-Ib, the genetic defect (black squares) leads to hormone resistance only if it is inherited from a female obligate carrier of the GNAS mutation. On the other hand, hormone resistance does not develop if the genetic defect is inherited from a male obligate carrier. Each black square indicates the mutation leading to PHP-Ia/PPHP or AD-PHP-Ib. Paternal and maternal alleles of the GNAS locus are depicted by white and gray rectangles, respectively. X’s indicate the silencing of paternal Gsα expression that occurs in a small number of cells, including those of the renal proximal tubules.