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Human Molecular Genetics Advance Access originally published online on November 10, 2004
Human Molecular Genetics 2005 14(1):95-102; doi:10.1093/hmg/ddi009
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Human Molecular Genetics, Vol. 14, No. 1 © Oxford University Press 2005; all rights reserved

Distinct patterns of abnormal GNAS imprinting in familial and sporadic pseudohypoparathyroidism type IB

Jie Liu, Julie G. Nealon{dagger} and Lee S. Weinstein*

Metabolic Diseases Branch, National Institute of Diabetes, Digestive and Kidney iseases, National Institutes of Health, Bethesda, MD 20892, USA

* To whom correspondence should be addressed. Tel: +1 3014022923; Fax: +1 3014020374; Email: leew{at}amb.niddk.nih.gov

Received September 14, 2004; Revised October 13, 2004; Accepted October 25, 2004

Pseudohypoparathyroidism type IB (PHPIB) is associated with abnormal imprinting of GNAS, the gene encoding the heterotrimeric G protein Gs{alpha} and other alternative products. The gene contains three differentially methylated regions (DMRs) located upstream of the Gs{alpha} promoter (from upstream to downstream): the paternally methylated NESP55 promoter region, the maternally methylated NESP antisense (NESPAS)/XL{alpha}s promoter region and the maternally methylated exon 1A region located just upstream of the Gs{alpha} promoter. We have now performed a detailed analysis of the GNAS methylation profile in 20 unrelated PHPIB probands. Consistent with prior results, all have loss of exon 1A imprinting (a paternal epigenotype on both alleles). All five probands with familial disease had a deletion mutation within the closely linked STX16 gene and a GNAS imprinting defect involving only the exon 1A region. In contrast, the STX16 mutation was absent in all sporadic cases. The majority of these patients had abnormal imprinting of the more upstream regions in addition to the exon 1A imprinting defect, with eight of 15 having a paternal epigenotype on both alleles throughout the GNAS locus. In virtually all cases, the imprinting status of the NESP55 and NESPAS/XL{alpha}s promoters is concordant, suggesting that their imprinting is co-regulated, whereas the imprinting of the NESPAS/XL{alpha}s promoter region and XL{alpha}s first exon is not always concordant even though they are closely linked and lie within the same DMR. Familial and sporadic forms of PHPIB have distinct GNAS imprinting patterns that occur through different defects in the imprinting mechanism.

{dagger} Present address: The Bullis School, Potomac, MD 20854, USA.


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