Autosomal dominant pseudohypoparathyroidism type Ib is associated with a heterozygous microdeletion that likely disrupts a putative imprinting control element of GNAS
J. Clin. Invest. Murat Bastepe, et al. 112:1255 doi:10.1172/JCI19159 [Go to this article.]

Figure 1
The GNAS locus and parent-of-origin–specific inheritance of hormone resistance. (a) GNAS gives rise, besides Gsα, to multiple other transcripts including NESP55, XLαs, the antisense (AS) and A/B (also referred to as 1A or 1′), all of which show differential methylation (asterisks) in their promoters and are expressed exclusively from the non-methylated paternal (p) or maternal (m) allele. Exons that lead to transcripts in the sense (right-pointing arrow) and antisense (left-pointing arrow) directions are depicted as black and gray boxes, respectively, and the splice patterns are indicated. Note that the promoter giving rise to the Gsα transcript, encoded by exons 1 through 13, does not show differential methylation. However, although expression is biallelic in most tissues, Gsα transcription from the paternal GNAS allele is proposed to be silenced in a limited number of cells (dotted arrow), including those in renal proximal tubules. (b) In kindreds with PHP-Ia and PPHP, as well as in those with AD-PHP-Ib, the genetic defect (black squares) leads to hormone resistance only if it is inherited from a female obligate carrier of the GNAS mutation. On the other hand, hormone resistance does not develop if the genetic defect is inherited from a male obligate carrier. Each black square indicates the mutation leading to PHP-Ia/PPHP or AD-PHP-Ib. Paternal and maternal alleles of the GNAS locus are depicted by white and gray rectangles, respectively. X’s indicate the silencing of paternal Gsα expression that occurs in a small number of cells, including those of the renal proximal tubules.