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

2.50
Hdl Handle:
http://hdl.handle.net/2336/15744
Title:
Autosomal dominant pseudohypoparathyroidism type Ib is associated with a heterozygous microdeletion that likely disrupts a putative imprinting control element of GNAS
Authors:
Bastepe, Murat; Fröhlich, Leopold F; Hendy, Geoffrey N; Indridason, Olafur S; Josse, Robert G; Koshiyama, Hiroyuki; Körkkö, Jarmo; Nakamoto, Jon M; Rosenbloom, Arlan L; Slyper, Arnold H; Sugimoto, Toshitsugu; Tsatsoulis, Agathocles; Crawford, John D; Jüppner, Harald
Citation:
J. Clin. Invest. 2003, 112(8):1255-63
Issue Date:
1-Oct-2003
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.
Description:
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Additional Links:
http://www.jci.org/cgi/content/abstract/112/8/1255

Full metadata record

DC FieldValue Language
dc.contributor.authorBastepe, Murat-
dc.contributor.authorFröhlich, Leopold F-
dc.contributor.authorHendy, Geoffrey N-
dc.contributor.authorIndridason, Olafur S-
dc.contributor.authorJosse, Robert G-
dc.contributor.authorKoshiyama, Hiroyuki-
dc.contributor.authorKörkkö, Jarmo-
dc.contributor.authorNakamoto, Jon M-
dc.contributor.authorRosenbloom, Arlan L-
dc.contributor.authorSlyper, Arnold H-
dc.contributor.authorSugimoto, Toshitsugu-
dc.contributor.authorTsatsoulis, Agathocles-
dc.contributor.authorCrawford, John D-
dc.contributor.authorJüppner, Harald-
dc.date.accessioned2008-01-07T14:52:03Z-
dc.date.available2008-01-07T14:52:03Z-
dc.date.issued2003-10-01-
dc.date.submitted2007-01-08-
dc.identifier.citationJ. Clin. Invest. 2003, 112(8):1255-63en
dc.identifier.issn0021-9738-
dc.identifier.pmid14561710-
dc.identifier.doi10.1172/JCI200319159-
dc.identifier.urihttp://hdl.handle.net/2336/15744-
dc.descriptionTo access full text version of this article. Please click on the hyperlink "Full Text" at the bottom of this pageen
dc.description.abstractPatients 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.en
dc.language.isoenen
dc.publisherAmerican Society for Clinical Investigationen
dc.relation.urlhttp://www.jci.org/cgi/content/abstract/112/8/1255en
dc.subject.meshAdolescenten
dc.subject.meshAdulten
dc.subject.meshChilden
dc.subject.meshDNA Methylationen
dc.subject.meshExonsen
dc.subject.meshGTP-Binding Protein alpha Subunits, Gsen
dc.subject.meshGene Deletionen
dc.subject.meshGenomic Imprintingen
dc.subject.meshHumansen
dc.subject.meshPedigreeen
dc.subject.meshPseudohypoparathyroidismen
dc.titleAutosomal dominant pseudohypoparathyroidism type Ib is associated with a heterozygous microdeletion that likely disrupts a putative imprinting control element of GNASen
dc.typeArticleen
dc.identifier.journalJournal of clinical investigationen
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