Maternal GNAS Contributes to the Extra-Large G Protein α-Subunit (XLαs) Expression in a Cell Type-Specific Manner
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-pseudohypop...
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Frontiers Media S.A.
2021-06-01
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| Series: | Frontiers in Genetics |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fgene.2021.680537/full |
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| author | Qiuxia Cui Qiuxia Cui Cagri Aksu Birol Ay Claire E. Remillard Antonius Plagge Mina Gardezi Margaret Dunlap Louis C. Gerstenfeld Qing He Qing He Murat Bastepe |
| author_facet | Qiuxia Cui Qiuxia Cui Cagri Aksu Birol Ay Claire E. Remillard Antonius Plagge Mina Gardezi Margaret Dunlap Louis C. Gerstenfeld Qing He Qing He Murat Bastepe |
| author_sort | Qiuxia Cui |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-08T11:10:51Z |
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| id | doaj.art-d9a3aa92a4074764a4d26e488c2cd8e9 |
| institution | Directory Open Access Journal |
| issn | 1664-8021 |
| language | English |
| last_indexed | 2024-03-08T11:10:51Z |
| publishDate | 2021-06-01 |
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| series | Frontiers in Genetics |
| spelling | doaj.art-d9a3aa92a4074764a4d26e488c2cd8e92024-01-26T12:12:03ZengFrontiers Media S.A.Frontiers in Genetics1664-80212021-06-011210.3389/fgene.2021.680537680537Maternal GNAS Contributes to the Extra-Large G Protein α-Subunit (XLαs) Expression in a Cell Type-Specific MannerQiuxia Cui0Qiuxia Cui1Cagri Aksu2Birol Ay3Claire E. Remillard4Antonius Plagge5Mina Gardezi6Margaret Dunlap7Louis C. Gerstenfeld8Qing He9Qing He10Murat Bastepe11Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United StatesDepartment of Thyroid and Breast Surgery, Zhongnan Hospital of Wuhan University, Wuhan, ChinaEndocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United StatesEndocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United StatesEndocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United StatesDepartment of Molecular Physiology and Cell Signalling, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, United KingdomDepartment of Orthopaedic Surgery, Boston University School of Medicine, Boston, MA, United StatesDepartment of Orthopaedic Surgery, Boston University School of Medicine, Boston, MA, United StatesDepartment of Orthopaedic Surgery, Boston University School of Medicine, Boston, MA, United StatesEndocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United StatesSchool of Stomatology, Wuhan University, Wuhan, ChinaEndocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United StatesGNAS 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.https://www.frontiersin.org/articles/10.3389/fgene.2021.680537/fullGNASstimulatory G proteinimprintingosteoblastsbone marrow stromal cellsfibrous dysplasia of bone |
| spellingShingle | Qiuxia Cui Qiuxia Cui Cagri Aksu Birol Ay Claire E. Remillard Antonius Plagge Mina Gardezi Margaret Dunlap Louis C. Gerstenfeld Qing He Qing He Murat Bastepe Maternal GNAS Contributes to the Extra-Large G Protein α-Subunit (XLαs) Expression in a Cell Type-Specific Manner Frontiers in Genetics GNAS stimulatory G protein imprinting osteoblasts bone marrow stromal cells fibrous dysplasia of bone |
| title | Maternal GNAS Contributes to the Extra-Large G Protein α-Subunit (XLαs) Expression in a Cell Type-Specific Manner |
| title_full | Maternal GNAS Contributes to the Extra-Large G Protein α-Subunit (XLαs) Expression in a Cell Type-Specific Manner |
| title_fullStr | Maternal GNAS Contributes to the Extra-Large G Protein α-Subunit (XLαs) Expression in a Cell Type-Specific Manner |
| title_full_unstemmed | Maternal GNAS Contributes to the Extra-Large G Protein α-Subunit (XLαs) Expression in a Cell Type-Specific Manner |
| title_short | Maternal GNAS Contributes to the Extra-Large G Protein α-Subunit (XLαs) Expression in a Cell Type-Specific Manner |
| title_sort | maternal gnas contributes to the extra large g protein α subunit xlαs expression in a cell type specific manner |
| topic | GNAS stimulatory G protein imprinting osteoblasts bone marrow stromal cells fibrous dysplasia of bone |
| url | https://www.frontiersin.org/articles/10.3389/fgene.2021.680537/full |
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