Physiological functions of the imprinted Gnas locus and its protein variants Gαs and XLαs in human and mouse

Abstract

The stimulatory a-subunit of trimeric G-proteins Ga s , which upon ligand binding to seven-transmembrane receptors activates adenylyl cyclases to produce the second messenger cAMP, constitutes one of the archetypal signal transduction molecules that have been studied in much detail. Over the past few years, however, genetic as well as biochemical approaches have led to a range of novel insights into the Ga s encoding guanine nucleotide binding protein, a-stimulating (Gnas) locus, its alternative protein products and its regulation by genomic imprinting, which leads to monoallelic, parental origin-dependent expression of the various transcripts. Here, we summarise the major characteristics of this complex gene locus and describe the physiological roles of Ga s and its 'extra large' variant XLa s at post-natal and adult stages as defined by genetic mutations. Opposite and potentially antagonistic functions of the two proteins in the regulation of energy homeostasis and metabolism have been identified in Gnasand Gnasxl (XLa s )-deficient mice, which are characterised by obesity and leanness respectively. A comparison of findings in mice with symptoms of the corresponding human genetic disease 'Albright's hereditary osteodystrophy'/'pseudohypoparathyroidism' indicates highly conserved functions as well as unresolved phenotypic differences.

Genomic imprinting and its relevance to congenital disease, infertility, molar pregnancy and induced pluripotent stem cell

“…[56][57][58][59] A remarkable finding with this disorder is that genetic mutations underlying the loss of methylation were initially mapped X56 kb upstream of the exon A/B ICR, indicating the presence of a longrange, cis-acting element. 56 Furthermore, heterozygous microdeletions at STX16, located approximately 220 kb upstream of the GNAS exon A/B ICR, were also found in most cases of autosomal dominant form of pseudohypoparathyroidism type Ib.…”

Targeted deletion of the Nesp55 DMR defines another Gnas imprinting control region and provides a mouse model of autosomal dominant PHP-Ib

“…GNAS encodes the α-subunit of the stimulatory G protein (Gsα), which is important for cAMP-dependent signaling events downstream of a large variety of G protein-coupled receptors (3)(4)(5)(6). By splicing three distinct first exons (A/B, XL, or NESP55; mouse exons 1A, Gnasxl, or Nesp55, respectively) onto GNAS exons 2 through 13 (mouse Gnas exons 2-12), several alternative transcripts are generated, including the paternally expressed sense transcripts XLαs, XXLαs, and A/B (in the mouse Xlαs, Xxlαs, and 1A, respectively) and the maternally expressed transcript NESP55 (in the mouse Nesp55) (7-9); furthermore, an antisense transcript AS [in the mouse, Nespas (10)] is expressed from the paternal allele (11).…”

“…The human disorders that are caused by heterozygous mutations within the GNAS locus include pseudohypoparathyroidism type Ia (PHP-Ia), which is caused by maternally inherited inactivating mutations affecting the exons encoding Gsα; pseudopseudohypoparathyroidism (PPHP) and progressive osseous heteroplasia (POH), which are both caused by paternally inherited inactivating mutations in these exons; and the McCune-Albright syndrome, which is caused by mutations that lead to constitutive Gsα activity (3)(4)(5)(6). Furthermore, the autosomal-dominant (AD) form of PHP type Ib (AD-PHP-Ib) is caused by microdeletions within or upstream of GNAS or by uniparental isodisomy of chromosome 20q, and both are associated with loss of one or several methylation imprints on the maternal GNAS allele (3).…”

“…Furthermore, the autosomal-dominant (AD) form of PHP type Ib (AD-PHP-Ib) is caused by microdeletions within or upstream of GNAS or by uniparental isodisomy of chromosome 20q, and both are associated with loss of one or several methylation imprints on the maternal GNAS allele (3). PHP-Ia is associated with multiple hormone resistance, including toward parathyroid hormone (PTH) and thyroid stimulating hormone (TSH), and Albright hereditary osteodystrophy (AHO) (3)(4)(5)(6). Like with PHP-Ia, patients affected by PHP-Ib develop resistance toward PTH leading to hypocalcemia and hyperphosphatemia, which can sometimes be associated with mild resistance to TSH; unlike PHP-Ia, PHP-Ib appears to be only rarely associated with AHO features, such as shortening of metacarpals (13)(14)(15).…”

“…Either of these epigenetic changes is associated, as determined in peripheral blood cells, with increased A/B transcription, which is thought to reduce Gsα expression in the proximal renal tubules, where this ubiquitous signaling protein appears to be derived predominantly from the maternal allele (6,15); as a result, PTH resistance develops in this tissue. Mice lacking the equivalent of one of the STX16 deletions failed to reproduce human AD-PHP-Ib, suggesting that the region important for establishing or maintaining exon A/B methylation is located at a different location in mice (19).…”