Human Molecular Genetics Advance Access published online on November 10, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddi009
© 2004 by Oxford University Press
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1 Metabolic Diseases Branch, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892 USA
* To whom correspondence should be addressed. Pseudohypoparathyroidism type IB (PHPIB) is associated with abnormal imprinting of GNAS, the gene encoding the heterotrimeric G protein Gs
Article
Distinct patterns of abnormal GNAS imprinting in familial and sporadic pseudohypoparathyroidism type IB
2 Metabolic Diseases Branch, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892 USA; The Bullis School, Potomac, MD 20854 USA
Lee S. Weinstein, E-mail: leew{at}amb.niddk.nih.gov
Abstract 
and other alternative products. The gene contains three differentially methylated regions located upstream of the Gs promoter (from upstream to downstream): the paternally methylated NESP55 promoter region, the maternally methylated NESP antisense (NESPAS)/XLs promoter, and the maternally methylated exon 1A region located just upstream of the Gs 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. In addition, the majority of these patients also had abnormal imprinting of the more upstream regions in addition to the exon 1A imprinting defect, with 8 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/XLs promoters are concordant, suggesting that their imprinting is coregulated, while the imprinting of the NESPAS/XLs promoter region and XLs first exon are not always concordant even though they are closely linked and lie within the same differentially methylated region. Familial and sporadic PHPIB have distinct GNAS imprinting patterns that occur through different defects in the imprinting mechanism.
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