GNAS complex locus

Products and functions

The GNAS locus is imprinted and encodes 5 main transcripts:

• 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. Abolition of expression causes abnormal methylation and imprinting loss.

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. 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. 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.

Clinical significance

Mutations in GNAS products are associated with:

• Albright hereditary osteodystrophy
• pseudohypoparathyroidism type Ia and Ib
• pseudopseudohypoparathyroidism
• McCune–Albright syndrome
• Myxoma

Mutations in this gene also result in progressive osseous heteroplasia, polyostotic fibrous dysplasia of bone, and some pituitary tumors. Mutations in the repeat region of the XL exon leads to a hyperactive form of XLas due to lowered interaction with ALEX. As XLas is expressed in platelets, the risk of bleeding is elevated.

Many alleles in mice have been constructed for analyzing disease associations. Mice with this gene half knocked-out and half-mutated (tm1Jop/Oedsml) display increased heart weight, increased startle reflex, and abnormalities in bone structure and mineralization; some other alternations can be lethal. Metabolic problems resembling pseudohypoparathyroidism are seen in heterozygous mutated (wt/Oedsml) mice. Knocking out the antisense transcript is known to, at minimum, cause methylation defects.

Interactions

G protein-coupled receptor-activated G_sα binds to the enzyme adenylyl cyclase, increasing its rate of conversion of ATP to cyclic AMP.

G_sα has been shown to interact with RIC8A.