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

Pseudohypoparathyroidism type IB (PHPIB) is associated with abnormal imprinting of GNAS, the gene encoding the heterotrimeric G protein G(s)alpha and other alternative products. The gene contains three differentially methylated regions (DMRs) located upstream of the G(s)alpha promoter (from upstream to downstream): the paternally methylated NESP55 promoter region, the maternally methylated NESP antisense (NESPAS)/XLalphas promoter region and the maternally methylated exon 1A region located just upstream of the G(s)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/XLalphas promoters is concordant, suggesting that their imprinting is co-regulated, whereas the imprinting of the NESPAS/XLalphas promoter region and XLalphas 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.