Alternative titles; symbols
HGNC Approved Gene Symbol: GNAS-AS1
Cytogenetic location: 20q13.32 Genomic coordinates (GRCh38) : 20:58,818,918-58,850,902 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20q13.32 | Pseudohypoparathyroidism Ib | 603233 | Autosomal dominant | 3 |
GNASAS1 is a paternally expressed antisense transcript of the GNAS complex locus (139320) (Hayward and Bonthron, 2000).
The GNAS locus has a highly complex imprinted expression pattern, with paternally, maternally and biallelically derived protein products. GNAS1 was originally identified as the gene encoding Gs-alpha, the alpha subunit of the stimulatory G protein. Gs-alpha is encoded by exons 1 to 13 of GNAS1 and, in most tissues, expression of this transcript is biallelic. However, 2 large upstream exons have monoallelic expression patterns, and in each case their transcripts splice onto GNAS1 exon 2. The most 5-prime of these is maternally expressed and encodes neuroendocrine secretory protein-55 (NESP55), whose coding region does not overlap with that of Gs-alpha. The other exon, 14 kb further 3-prime, is paternally expressed and encodes XL-alpha-s, which is translated in-frame with Gs-alpha exons 2 to 13. Hayward and Bonthron (2000) identified a spliced polyadenylated antisense transcript arising from the maternally methylated region upstream of the XL-alpha-s exon, which spans the upstream NESP55 region. The antisense transcript is imprinted, and expressed only from the paternal allele, suggesting to the authors that it may have a specific role in suppressing in cis the activity of the paternal NESP55 allele.
The Gnas locus in distal mouse chromosome 2 is a complex genomic region. It contains 3 imprinted genes in the order Nesp-Gnasxl-Gnas. The first 2 genes encode proteins expressed in neuroendocrine tissue. Together, these genes form a single transcription unit because transcripts of Nesp and Gnasxl are alternatively spliced onto exon 2 of Gnas. Nesp and Gnasxl are expressed from opposite parental alleles, with Nesp encoding a maternal-specific transcript and Gnasxl encoding a paternal-specific transcript. Wroe et al. (2000) identified a further imprinted transcript in this cluster. RT-PCR analysis of Nesp expression in 15.5 day-postcoitum embryos carrying only maternal or paternal copies of distal chromosome 2 revealed an isoform that is exclusively paternally, rather than maternally, expressed. Strand-specific RT-PCR showed that this form is an antisense transcript. The existence of a paternally expressed antisense transcript was confirmed by Northern blot analysis. The sequence is contiguous with genomic sequence downstream of Nesp and encompasses Nesp exons 1 and 2 and an intervening intron. Wroe et al. (2000) proposed that Nespas (as they designated the antisense gene) is an additional control element in the imprinting region of mouse distal chromosome 2.
Genomic imprinting results in allele-specific silencing according to parental origin. Silencing is brought about by imprinting control regions (ICRs) that are differentially marked in gametogenesis. Williamson et al. (2006) noted that a previously identified ICR specifically regulates tissue-specific imprinted expression of the mouse Gnas cluster. They identified a second ICR at the Gnas cluster. Williamson et al. (2006) showed that a paternally-derived targeted deletion of the germline differentially methylated region (DMR) associated with the antisense Nespas transcript unexpectedly affected both the expression of all transcripts in the cluster and methylation of 2 DMRs. The results established that the Nespas DMR is the principal ICR at the Gnas cluster and functions bidirectionally as a switch for modulating expression of the antagonistically acting genes Gnasxl and Gnas. Uniquely, the Nespas DMR acts on the downstream ICR at exon 1A to regulate tissue-specific imprinting of the Gnas gene.
Gene-Environment Interaction
Prenatal famine in humans has been associated with various consequences in later life, depending on the gestational timing of the insult and the sex of the exposed individual. Epigenetic mechanisms have been proposed to underlie these associations. Tobi et al. (2009) investigated the methylation of 15 loci implicated in growth and metabolic disease in individuals who were prenatally exposed to war-time famine in the Netherlands from 1944 to 1945. Methylation of INSIGF (see INS, 176730), which is an alternately spliced read-through transcript of INS and IGF2 (147470), was lower among 60 individuals who were periconceptionally exposed to the famine compared to 60 of their unexposed same-sex sibs, whereas methylation of IL10 (124092), LEP (164160), ABCA1 (600046), GNASAS, and MEG3 (605636) was higher than control. A significant interaction with sex was observed for INSIGF, LEP, and GNASAS. When methylation of 8 representative loci was compared between 62 individuals exposed late in gestation and 62 of their unexposed sibs, methylation was different for GNASAS in both men and women, and LEP methylation was different in men only. Tobi et al. (2009) concluded that persistent changes in DNA methylation may be a common consequence of prenatal famine exposure, and that these changes may depend on the sex of the exposed individual and the gestational timing of the exposure.
GNASAS is an antisense transcript of the GNAS complex locus, which maps to chromosome 20q13 in human and to chromosome 2 in mouse (Hayward and Bonthron, 2000; Wroe et al., 2000).
In affected members of 2 unrelated kindreds with pseudohypoparathyroidism type Ib (PHP Ib; 603233), Bastepe et al. (2005) identified a 4.7-kb deletion removing the entire NESP55 DMR in the GNAS locus (139320.0031) and exons 3 and 4 of the GNAS antisense transcript (610540.0001). Maternal inheritance of the deletion caused loss of imprinting in cis at the entire GNAS locus.
In 2 unrelated kindreds with pseudohypoparathyroidism type Ib (603233), Bastepe et al. (2005) identified a 4.7-kb deletion that removed the differentially methylated region of the GNAS gene (139320.0031) encompassing the NESP55 region and exons 3 and 4 of the GNAS antisense transcript. When inherited from a female, the deletion abolished all maternal GNAS imprints and derepressed maternally silenced transcripts, suggesting that the deleted region contains a cis-acting element that controls imprinting of the maternal GNAS allele.
Bastepe, M., Frohlich, L. F., Linglart, A., Abu-Zahra, H. S., Tojo, K., Ward, L. M., Juppner, H. Deletion of the NESP55 differentially methylated region causes loss of maternal GNAS imprints and pseudohypoparathyroidism type Ib. Nature Genet. 37: 25-27, 2005. [PubMed: 15592469] [Full Text: https://doi.org/10.1038/ng1487]
Hayward, B. E., Bonthron, D. T. An imprinted antisense transcript at the human GNAS1 locus. Hum. Molec. Genet. 9: 835-841, 2000. [PubMed: 10749992] [Full Text: https://doi.org/10.1093/hmg/9.5.835]
Tobi, E. W., Lumey, L. H., Talens, R. P., Kremer, D., Putter, H., Stein, A. D., Slagboom, P. E., Heijmans, B. T. DNA methylation differences after exposure to prenatal famine are common and timing- and sex-specific. Hum. Molec. Genet. 18: 4046-4053, 2009. [PubMed: 19656776] [Full Text: https://doi.org/10.1093/hmg/ddp353]
Williamson, C. M., Turner, M. D., Ball, S. T., Nottingham, W. T., Glenister, P., Fray, M., Tymowska-Lalanne, Z., Plagge, A., Powles-Glover, N., Kelsey, G., Maconochie, M., Peters, J. Identification of an imprinting control region affecting the expression of all transcripts in the Gnas cluster. Nature Genet. 38: 350-355, 2006. [PubMed: 16462745] [Full Text: https://doi.org/10.1038/ng1731]
Wroe, S. F., Kelsey, G., Skinner, J. A., Bodle, D., Ball, S. T., Beechey, C. V., Peters, J., Williamson, C. M. An imprinted transcript, antisense to Nesp, adds complexity to the cluster of imprinted genes at the mouse Gnas locus. Proc. Nat. Acad. Sci. 97: 3342-3346, 2000. [PubMed: 10716699] [Full Text: https://doi.org/10.1073/pnas.97.7.3342]