A Novel T55A Variant of Gsα Associated with Impaired cAMP Production, Bone Fragility, and Osteolysis
G-protein coupled receptors (GPCRs) mediate a wide spectrum of biological activities. The GNAS complex locus encodes the stimulatory alpha subunit of the guanine nucleotide binding protein (Gsα) and regulates production of the second messenger cyclic AMP (cAMP). Loss-of-function GNAS mutations class...
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| Format: | Article |
| Language: | English |
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Wiley
2016-01-01
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| Series: | Case Reports in Endocrinology |
| Online Access: | http://dx.doi.org/10.1155/2016/2691385 |
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| author | Kelly Wentworth Alyssa Hsing Ashley Urrutia Yan Zhu Andrew E. Horvai Murat Bastepe Edward C. Hsiao |
| author_facet | Kelly Wentworth Alyssa Hsing Ashley Urrutia Yan Zhu Andrew E. Horvai Murat Bastepe Edward C. Hsiao |
| author_sort | Kelly Wentworth |
| collection | DOAJ |
| description | G-protein coupled receptors (GPCRs) mediate a wide spectrum of biological activities. The GNAS complex locus encodes the stimulatory alpha subunit of the guanine nucleotide binding protein (Gsα) and regulates production of the second messenger cyclic AMP (cAMP). Loss-of-function GNAS mutations classically lead to Albright’s Hereditary Osteodystrophy (AHO) and pseudohypoparathyroidism, often with significant effects on bone formation and mineral metabolism. We present the case of a child who exhibits clinical features of osteolysis, multiple childhood fractures, and neonatal SIADH. Exome sequencing revealed a novel de novo heterozygous missense mutation of GNAS (c.163A<G, p.T55A) affecting the p-loop of the catalytic Gsα GTPase domain. In order to further assess whether this unique mutation resulted in a gain or loss of function of Gsα, we introduced the mutation into a rat GNAS plasmid and performed functional studies to assess the level of cAMP activity associated with this mutation. We identified a 64% decrease in isoproterenol-induced cAMP production in vitro, compared to wild type, consistent with loss of Gsα activity. Despite a significant decrease in isoproterenol-induced cAMP production in vitro, this mutation did not produce a classical AHO phenotype in our patient; however, it may account for her presentation with childhood fractures and osteolysis. |
| format | Article |
| id | doaj-art-3872595dc2c64eafbfbd1d45333ce35c |
| institution | Kabale University |
| issn | 2090-6501 2090-651X |
| language | English |
| publishDate | 2016-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Case Reports in Endocrinology |
| spelling | doaj-art-3872595dc2c64eafbfbd1d45333ce35c2025-08-20T03:55:11ZengWileyCase Reports in Endocrinology2090-65012090-651X2016-01-01201610.1155/2016/26913852691385A Novel T55A Variant of Gsα Associated with Impaired cAMP Production, Bone Fragility, and OsteolysisKelly Wentworth0Alyssa Hsing1Ashley Urrutia2Yan Zhu3Andrew E. Horvai4Murat Bastepe5Edward C. Hsiao6Division of Endocrinology, Diabetes, and Metabolism and The Institute for Human Genetics, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USADivision of Endocrinology, Diabetes, and Metabolism and The Institute for Human Genetics, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USADivision of Endocrinology, Diabetes, and Metabolism and The Institute for Human Genetics, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USAEndocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USADepartments of Pathology and Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USAEndocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USADivision of Endocrinology, Diabetes, and Metabolism and The Institute for Human Genetics, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USAG-protein coupled receptors (GPCRs) mediate a wide spectrum of biological activities. The GNAS complex locus encodes the stimulatory alpha subunit of the guanine nucleotide binding protein (Gsα) and regulates production of the second messenger cyclic AMP (cAMP). Loss-of-function GNAS mutations classically lead to Albright’s Hereditary Osteodystrophy (AHO) and pseudohypoparathyroidism, often with significant effects on bone formation and mineral metabolism. We present the case of a child who exhibits clinical features of osteolysis, multiple childhood fractures, and neonatal SIADH. Exome sequencing revealed a novel de novo heterozygous missense mutation of GNAS (c.163A<G, p.T55A) affecting the p-loop of the catalytic Gsα GTPase domain. In order to further assess whether this unique mutation resulted in a gain or loss of function of Gsα, we introduced the mutation into a rat GNAS plasmid and performed functional studies to assess the level of cAMP activity associated with this mutation. We identified a 64% decrease in isoproterenol-induced cAMP production in vitro, compared to wild type, consistent with loss of Gsα activity. Despite a significant decrease in isoproterenol-induced cAMP production in vitro, this mutation did not produce a classical AHO phenotype in our patient; however, it may account for her presentation with childhood fractures and osteolysis.http://dx.doi.org/10.1155/2016/2691385 |
| spellingShingle | Kelly Wentworth Alyssa Hsing Ashley Urrutia Yan Zhu Andrew E. Horvai Murat Bastepe Edward C. Hsiao A Novel T55A Variant of Gsα Associated with Impaired cAMP Production, Bone Fragility, and Osteolysis Case Reports in Endocrinology |
| title | A Novel T55A Variant of Gsα Associated with Impaired cAMP Production, Bone Fragility, and Osteolysis |
| title_full | A Novel T55A Variant of Gsα Associated with Impaired cAMP Production, Bone Fragility, and Osteolysis |
| title_fullStr | A Novel T55A Variant of Gsα Associated with Impaired cAMP Production, Bone Fragility, and Osteolysis |
| title_full_unstemmed | A Novel T55A Variant of Gsα Associated with Impaired cAMP Production, Bone Fragility, and Osteolysis |
| title_short | A Novel T55A Variant of Gsα Associated with Impaired cAMP Production, Bone Fragility, and Osteolysis |
| title_sort | novel t55a variant of gsα associated with impaired camp production bone fragility and osteolysis |
| url | http://dx.doi.org/10.1155/2016/2691385 |
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