Abstract
GNAS encodes the stimulatory G protein alpha-subunit (Gsα) and its large variant XLαs. Studies have suggested that XLαs is expressed exclusively paternally. Thus, XLαs deficiency is considered to be responsible for certain findings in patients with paternal GNAS mutations, such as pseudo-pseudohypoparathyroidism, and the phenotypes associated with maternal uniparental disomy of chromosome 20, which comprises GNAS. However, a study of bone marrow stromal cells (BMSC) suggested that XLαs could be biallelically expressed. Aberrant BMSC differentiation due to constitutively activating GNAS mutations affecting both Gsα and XLαs is the underlying pathology in fibrous dysplasia of bone. To investigate allelic XLαs expression, we employed next-generation sequencing and a polymorphism common to XLαs and Gsα, as well as A/B, another paternally expressed GNAS transcript. In mouse BMSCs, Gsα transcripts were 48.4 ± 0.3% paternal, while A/B was 99.8 ± 0.2% paternal. In contrast, XLαs expression varied among different samples, paternal contribution ranging from 43.0 to 99.9%. Sample-to-sample variation in paternal XLαs expression was also detected in bone (83.7–99.6%) and cerebellum (83.8 to 100%) but not in cultured calvarial osteoblasts (99.1 ± 0.1%). Osteoblastic differentiation of BMSCs shifted the paternal XLαs expression from 83.9 ± 1.5% at baseline to 97.2 ± 1.1%. In two human BMSC samples grown under osteoinductive conditions, XLαs expression was also predominantly monoallelic (91.3 or 99.6%). Thus, the maternal GNAS contributes significantly to XLαs expression in BMSCs but not osteoblasts. Altered XLαs activity may thus occur in certain cell types irrespective of the parental origin of a GNAS defect.
Highlights
GNAS is an imprinted gene encoding the alpha-subunit of the stimulatory G protein (Gsα), a signaling protein mediating the actions of many endogenous molecules via generation of cAMP (Plagge et al, 2008; Weinstein et al, 2004; Mantovani et al, 2016)
Gain-of-function GNAS mutations affecting the activity of Gsα are found in a variety of benign and malignant tumors, as well as in patients with fibrous dysplasia of bone and McCune-Albright syndrome (MIM: 174800)
Our results revealed a significant contribution from the maternal GNAS allele in nondifferentiated bone marrow stromal cells (BMSC) but not in osteogenically differentiated BMSCs or calvarial osteoblasts
Summary
GNAS is an imprinted gene encoding the alpha-subunit of the stimulatory G protein (Gsα), a signaling protein mediating the actions of many endogenous molecules via generation of cAMP (Plagge et al, 2008; Weinstein et al, 2004; Mantovani et al, 2016). Gain-of-function GNAS mutations affecting the activity of Gsα are found in a variety of benign and malignant tumors, as well as in patients with fibrous dysplasia of bone and McCune-Albright syndrome (MIM: 174800). XLαs is partly identical to Gsα and can mimic the latter regarding cAMP generation (Klemke et al, 2000; Bastepe et al, 2002); XLαs mediates additional cellular actions, such as stimulation of IP3/PKC signaling and inhibition of clathrin-mediated endocytosis (He et al, 2015; He et al, 2017; He et al, 2019)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
