Autosomal dominant pseudohypoparathyroidism type Ib is associated with a heterozygous microdeletion that likely disrupts a putative imprinting control element of GNAS
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Fröhlich, Leopold F
Hendy, Geoffrey N
Indridason, Olafur S
Josse, Robert G
Nakamoto, Jon M
Rosenbloom, Arlan L
Slyper, Arnold H
Crawford, John D
MetadataShow full item record
CitationJ. Clin. Invest. 2003, 112(8):1255-63
ÚtdrátturPatients 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.
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- A novel STX16 deletion in autosomal dominant pseudohypoparathyroidism type Ib redefines the boundaries of a cis-acting imprinting control element of GNAS.
- Authors: Linglart A, Gensure RC, Olney RC, Jüppner H, Bastepe M
- Issue date: 2005 May
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- Lack of Gnas epigenetic changes and pseudohypoparathyroidism type Ib in mice with targeted disruption of syntaxin-16.
- Authors: Fröhlich LF, Bastepe M, Ozturk D, Abu-Zahra H, Jüppner H
- Issue date: 2007 Jun
- GNAS epigenetic defects and pseudohypoparathyroidism: time for a new classification?
- Authors: Mantovani G, Elli FM, Spada A
- Issue date: 2012 Sep
- Phenotypic and molecular genetic aspects of pseudohypoparathyroidism type Ib in a Greek kindred: evidence for enhanced uric acid excretion due to parathyroid hormone resistance.
- Authors: Laspa E, Bastepe M, Jüppner H, Tsatsoulis A
- Issue date: 2004 Dec