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Pseudohypoparathyroidism Image courtesy O.Chaigasame

Albright’s hereditary osteodystrophy (AHO) and characteristic skeletal abnormalities. A) A child with AHO exhibiting short stature, obesity, and round facies. B) The hand X-ray of a patient with AHO, displaying brachydactyly of the fourth and fifth metacarpal bones. C) Dimpling over the knuckles of a clenched fist (also known as Archibald sign), indicating the short metacarpals. D) Evidence of brachydactyly in the hand, reflecting the shortened fourth and fifth metacarpals and the distal phalanx of the thumb. Images are from: Levine, MA. (139).

Simplified view of the GNAS region and its transcripts. The normal allele-specific methylation and expression patterns of the four alternate first exons of GNAS which splice onto exon 2 to produce transcripts encoding NESP55, XLαs, 1A (referred to as A/B in humans), and Gsα (which uses exon 1). NESP55 and XLαs promoters are oppositely imprinted: NESP55 is expressed from the maternal allele and its promoter region is methylated on the paternal allele, whereas XLαs is expressed from the paternal allele and its promoter is methylated on the maternal allele. Gsα is paternally silenced in some tissues e.g., renal proximal tubule cells, indicated by the dashed arrow. NESP55 protein is unrelated to Gsα, and its entire coding region is located within its first exon. In contrast, XLαs and Gsα proteins have identical COOH-terminal domains (encoded by exons 2-13), while their unique NH2-terminal domains are encoded within their respective first exons. Exon A/B (1A) does not have a translational start site but is transcriptionally active. Loss of exon A/B imprinting (methylation) is associated with decreased Gsα expression in renal proximal tubules and some other hormone-responsive tissues and is the typical cause of PHP1B. (figure from Liu et al., 2000, with permission).