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Bastepe, M; Fröhlich, LF; Hendy, GN; Indridason, OS; Josse, RG; Koshiyama, H; Körkkö, J; Nakamoto, JM; Rosenbloom, AL; Slyper, AH; Sugimoto, T; Tsatsoulis, A; Crawford, JD; Jüppner, H.
Autosomal dominant pseudohypoparathyroidism type Ib is associated with a heterozygous microdeletion that likely disrupts a putative imprinting control element of GNAS.
J Clin Invest. 2003; 112(8): 1255-1263. Doi: 10.1172/JCI19159 [OPEN ACCESS]
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Co-authors Med Uni Graz: Fröhlich Leopold F.
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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 alpha 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.
Find related publications in this database (using NLM MeSH Indexing): Adolescent -; Adult -; Child -; DNA Methylation -; Exons -; GTP-Binding Protein alpha Subunits, Gs - genetics; Gene Deletion - genetics; Genomic Imprinting - genetics; Humans - genetics; Pedigree - genetics; Pseudohypoparathyroidism - genetics