GNAS Spectrum of Disorders

Abstract

The GNAS complex locus encodes the alpha-subunit of the stimulatory G protein (Gsα), a ubiquitous signaling protein mediating the actions of many hormones, neurotransmitters, and paracrine/autocrine factors via generation of the second messenger cAMP. GNAS gives rise to other gene products, most of which exhibit exclusively monoallelic expression. In contrast, Gsα is expressed biallelically in most tissues; however, paternal Gsα expression is silenced in a small number of tissues through as-yet-poorly understood mechanisms that involve differential methylation within GNAS. Gsα-coding GNAS mutations that lead to diminished Gsα expression and/or function result in Albright's hereditary osteodystrophy (AHO) with or without hormone resistance, i.e., pseudohypoparathyroidism type-Ia/Ic and pseudo-pseudohypoparathyroidism, respectively. Microdeletions that alter GNAS methylation and, thereby, diminish Gsα expression in tissues in which the paternal Gsα allele is normally silenced also cause hormone resistance, which occurs typically in the absence of AHO, a disorder termed pseudohypoparathyroidism type-Ib. Mutations of GNAS that cause constitutive Gsα signaling are found in patients with McCune-Albright syndrome, fibrous dysplasia of bone, and different endocrine and non-endocrine tumors. Clinical features of these diseases depend significantly on the parental allelic origin of the GNAS mutation, reflecting the tissue-specific paternal Gsα silencing. In this article, we review the pathogenesis and the phenotypes of these human diseases.

Figure 1. Multiple imprinted sense and antisense transcripts from the GNAS complex locus

Exons 1–13 encode Gsα, which is biallelic in most tissues; however, paternal Gsα allele is silenced in certain tissues (dotted arrow). Several other transcripts arise from differentially methylated promoters, including the maternally expressed NESP55 and the paternally expressed XLαs and A/B (also referred to as 1A or 1’). All of these transcripts use individual first exons that splice onto exons 2–13 of GNAS. Another non-coding transcript is also derived from the paternal GNAS allele, but this transcript is made from the antisense strand (GNAS-AS1 transcript, also referred to as Nespas in mice). Boxes and connecting lines depict exons and introns, respectively. Maternal (mat) and paternal (pat) GNAS products are illustrated above and below the gene structure, respectively, with splicing patterns indicated by broken lines. “+” indicates methylated promoters either on the paternal allele (NESP55) or the maternal allele (XLαs, A/B, GNAS-AS1 exon 1). Arrows indicate direction of transcription. The figure is not drawn to scale.

Figure 2. Genetic defects underlying the different GNAS-related disorders

Mutations scattered through all Gsα-coding GNAS exons cause AHO (Albrigh’s hereditary osteodystrophy) with or without hormone resistance, i.e. pseudohypoparathyroidism (PHP)-Ia, PHP-Ic, pseudopseudohypoparathyroidism (PPHP), or progressive ossesous heteroplasia (POH). Maternal STX16 deletions cause isolated A/B loss of methylation; maternal deletion of NESP55 leads to isolated A/B loss of methylation with hemizygosity in NESP55. Maternal deletions affecting GNAS-AS1 (AS) exons 3 and 4 result in a loss of methylation at all maternal GNAS imprints. Sporadic PHP-Ib cases show loss of methylation at exon XL, the promoter of GNAS-AS1, and exon A/B, and a gain of methylation at exon NESP55, but the genetic defect is unknown except for paternal uniparental disomy involving chromosome 20q. Missense mutations of residues Arg201 and Gln227 cause McCune-Albright Syndrome (MAS) and fibrous dysplasia of bone (FD) and are found in various endocrine and non-endocrine tumors. Boxes and connecting lines depict exons and introns, respectively. Maternal (mat) and paternal (pat) GNAS products are indicated by their direction of transcription. Arrows indicate direction of transcription; dotted arrow is used to indicate the tissue-specific paternal silencing of Gsα. The figure is not drawn to scale.

Figure 3. A scheme of differential diagnosis for patients who present with AHO and/or hormone resistance

DNA testing for GNAS mutations is conducted in a variety of commercial laboratories (see Genetic Testing Registry; www.ncbi.nlm.nih.gov/gtr/tests). PPHP, pseudopseudohypoparathyroidism; PHP, pseudohypoparathyroidism; AD-PHP-Ib, autosomal dominant pseudohypoparathyroidism; LOM, loss of methylation; LOH, loss of heterozygosity; patUPD20q, paternal uniparental disomy affecting the region of chromosome 20 that comprises GNAS; AS E3/4, GNAS-AS1 exons 3 and 4. *, if Albright’s hereditary osteodystrophy (AHO) features include heterotopic ossification that invades the deep connective tissue and skeletal muscle, then the diagnosis is progressive osseous heteroplasia (POH). Note that patients with POH infrequently display other AHO features or hormone resistance. **, LOH can also be detected if there is a large deletion on the maternal allele that removes all the GNAS differentially methylated regions.