Molecular Deconvolution Platform to Establish Disease Mechanisms by Surveying GPCR Signaling

• Published in: Cell reports (Cambridge) Vol. 24; no. 3; pp. 557 - 568.e5
• Main Authors: Masuho, Ikuo, Chavali, Sreenivas, Muntean, Brian S., Skamangas, Nickolas K., Simonyan, Kristina, Patil, Dipak N., Kramer, Grant M., Ozelius, Laurie, Babu, M. Madan, Martemyanov, Kirill A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.07.2018; Cell Press; Elsevier
• Subjects: Adenylyl Cyclases - metabolism; Animals; Disease - genetics; GTP Phosphohydrolases - metabolism; GTP-Binding Proteins - chemistry; GTP-Binding Proteins - genetics; GTP-Binding Proteins - metabolism; HEK293 Cells; Humans; Mice, Inbred C57BL; Models, Molecular; Mutation - genetics; Nucleotides - metabolism; Protein Domains; Protein Multimerization; Protein Stability; Receptors, G-Protein-Coupled - metabolism; Signal Transduction
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2018.06.080

Despite the wealth of genetic information available, mechanisms underlying pathological effects of disease-associated mutations in components of G protein-coupled receptor (GPCR) signaling cascades remain elusive. In this study, we developed a scalable approach for the functional analysis of clinical variants in GPCR pathways along with a complete analytical framework. We applied the strategy to evaluate an extensive set of dystonia-causing mutations in G protein Gαolf. Our quantitative analysis revealed diverse mechanisms by which pathogenic variants disrupt GPCR signaling, leading to a mechanism-based classification of dystonia. In light of significant clinical heterogeneity, the mechanistic analysis of individual disease-associated variants permits tailoring personalized intervention strategies, which makes it superior to the current phenotype-based approach. We propose that the platform developed in this study can be universally applied to evaluate disease mechanisms for conditions associated with genetic variation in all components of GPCR signaling. [Display omitted] •A scalable platform allows multidimensional analysis of GPCR signaling•The approach is applied to dystonia-causing mutations in G protein Gαolf•Pathogenic variants in Gαolf disrupt GPCR signaling by diverse mechanisms•Mechanism-based disease classification could allow targeted therapies Masuho et al. report development of a scalable platform for functional analysis of variants in GPCR pathway components. They apply the method to interrogate molecular mechanisms of dystonia by surveying an exhaustive set of clinical variants in Gαolf revealing diversity of mechanisms underlying signaling disruptions and offering mechanism-based disease classification.