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 2

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The AD-PHP-Ib critical interval. The AD-PHP-Ib genetic interval was dete...
The AD-PHP-Ib critical interval. The AD-PHP-Ib genetic interval was determined by recombination events in kindreds W (centromeric [cen]) and F (telomeric [tel]). Boundary markers are underlined; microsatellites are in italics. While the distance between 907-Rep2 and 806M20-119516 is about 300 kb, the region between 806M20-98760 and 806M20-119516 has been previously excluded through direct sequence analysis (23). Thus, the critical interval comprises approximately 280 kb. Note that 261P9-CA1 is a dinucleotide repeat located within intron 6 of STX16. Known and predicted genes within the linked interval are depicted as filled or open boxes, respectively (note that individual exons are not shown). For GNAS, exons are shown with black (sense) and gray (antisense) boxes (N, exon NESP55; A, exons encoding an antisense transcript; X, exon XL; A/B, exon A/B; 1–13, exons encoding Gsα). MGC4294 (National Center for Biotechnology Information locus ID: 79160) and NPEPL1 (locus ID: 79716) are predicted genes. Note that the centromeric boundary of the AD-PHP-Ib locus was previously defined at D20S149 (22, 23). However, the daughter of W-II/9 in kindred W (23) was shown to have a loss of exon A/B methylation, making the recombination event in W-II/9 informative, which redefined the centromeric boundary at 907-Rep2.