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Case Reports in Endocrinology
Volume 2016, Article ID 2691385, 6 pages
Case Report

A Novel T55A Variant of Gsα Associated with Impaired cAMP Production, Bone Fragility, and Osteolysis

1Division of Endocrinology, Diabetes, and Metabolism and The Institute for Human Genetics, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
2Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
3Departments of Pathology and Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA

Received 28 February 2016; Revised 3 June 2016; Accepted 3 July 2016

Academic Editor: Hidetoshi Ikeda

Copyright © 2016 Kelly Wentworth et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


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 () 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 GTPase domain. In order to further assess whether this unique mutation resulted in a gain or loss of function of , 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 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.