GNAS complex locus

GNAS complex locus is a gene locus in humans. Its main product is the

• G_s-α (G_s-α long, P63092-1), biallelic
• A/B transcript (G_s-α short, P63092-2), biallelic: contains an alternate 5' terminal exon (A/B or Exon 1A) and uses a downstream start codon to have a shortened amino terminal region.
  • STX16 deletion causes loss of methylation at the A/B exon, leading to PHP1B.
• XLαs (Extra long alpha-s, Q5JWF2), paternal
  • ALEX (Alternative gene product encoded by XL-exon, P84996), may inhibit XLαs
• NESP55 (Neuroendocrine secretory protein 55, O95467), maternal
• antisense GNAS transcript (Nespas: neuroendocrine secretory protein antisense)
  • Binds to the PRC2 complex.^[8] Abolition of expression causes abnormal methylation and imprinting loss.^[9]

Alternative splicing of downstream exons is also observed, which results in different forms of the G_s-α, a key element of the classical signal transduction pathway linking receptor-ligand interactions with the activation of adenylyl cyclase and a variety of cellular responses. Multiple transcript variants have been found for this gene, but the full-length nature and/or biological validity of some variants have not been determined.

Three of the GNAS gene products, G_sα-long, G_sα-short, and XLαs, are different forms of G_sα, and differ mainly in the N-terminal region. Traditional G protein-coupled receptor signaling proceeds primarily through G_sα-long and G_sα-short, the most abundant, ubiquitously-expressed protein products of this gene. XLαs is the "extra large" isoform, and has a very long N-terminal region with some internal repeats not well-conserved across species. The XL exon also encodes in another reading frame the protein product ALEX, an inhibitory cofactor binding to the unique domain.^[10][7] The structure for GNAS is solved for the canonical P63092-1 isoform only, and little is known about what the special region of XLas or ALEX looks like.

NESP55 is a protein product completely unrelated to the GNAS protein. It undergoes extensive posttranslation processing, and is sometimes grouped as a granin.^[11] Nearly nothing is known about its structure; protein structure prediction predicts a mostly disordered protein with an N-terminal globular domain made up of alpha-helices.^[12][13]

Clinical significance

Mutations in GNAS products are associated with:

• Albright hereditary osteodystrophy
• pseudohypoparathyroidism type Ia and Ib
• pseudopseudohypoparathyroidism
• McCune–Albright syndrome
• Myxoma^[14]

Mutations in this gene also result in