Molecular Deconvolution Platform to Establish Disease Mechanisms by Surveying GPCR Signaling
Summary: 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 o...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2018-07-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124718310076 |
| _version_ | 1811238436977246208 |
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| author | Ikuo Masuho Sreenivas Chavali Brian S. Muntean Nickolas K. Skamangas Kristina Simonyan Dipak N. Patil Grant M. Kramer Laurie Ozelius M. Madan Babu Kirill A. Martemyanov |
| author_facet | Ikuo Masuho Sreenivas Chavali Brian S. Muntean Nickolas K. Skamangas Kristina Simonyan Dipak N. Patil Grant M. Kramer Laurie Ozelius M. Madan Babu Kirill A. Martemyanov |
| author_sort | Ikuo Masuho |
| collection | DOAJ |
| description | Summary: 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. : 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. |
| first_indexed | 2024-04-12T12:41:32Z |
| format | Article |
| id | doaj.art-65408cab4e754f23b07532e669c3c57d |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-04-12T12:41:32Z |
| publishDate | 2018-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-65408cab4e754f23b07532e669c3c57d2022-12-22T03:32:45ZengElsevierCell Reports2211-12472018-07-01243557568.e5Molecular Deconvolution Platform to Establish Disease Mechanisms by Surveying GPCR SignalingIkuo Masuho0Sreenivas Chavali1Brian S. Muntean2Nickolas K. Skamangas3Kristina Simonyan4Dipak N. Patil5Grant M. Kramer6Laurie Ozelius7M. Madan Babu8Kirill A. Martemyanov9Department of Neuroscience, The Scripps Research Institute Florida, Jupiter, FL 33458, USAMRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UKDepartment of Neuroscience, The Scripps Research Institute Florida, Jupiter, FL 33458, USADepartment of Neuroscience, The Scripps Research Institute Florida, Jupiter, FL 33458, USADepartment of Otolaryngology, Harvard Medical School and Massachusetts Eye and Ear, Boston, MA 02114, USADepartment of Neuroscience, The Scripps Research Institute Florida, Jupiter, FL 33458, USADepartment of Neuroscience, The Scripps Research Institute Florida, Jupiter, FL 33458, USA; Harriet L. Wilkes Honors College, Florida Atlantic University, Jupiter, FL 33458, USADepartment of Neurology, Harvard Medical School and Massachusetts General Hospital, Charlestown, MA 02129, USAMRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UKDepartment of Neuroscience, The Scripps Research Institute Florida, Jupiter, FL 33458, USA; Corresponding authorSummary: 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. : 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.http://www.sciencedirect.com/science/article/pii/S2211124718310076 |
| spellingShingle | Ikuo Masuho Sreenivas Chavali Brian S. Muntean Nickolas K. Skamangas Kristina Simonyan Dipak N. Patil Grant M. Kramer Laurie Ozelius M. Madan Babu Kirill A. Martemyanov Molecular Deconvolution Platform to Establish Disease Mechanisms by Surveying GPCR Signaling Cell Reports |
| title | Molecular Deconvolution Platform to Establish Disease Mechanisms by Surveying GPCR Signaling |
| title_full | Molecular Deconvolution Platform to Establish Disease Mechanisms by Surveying GPCR Signaling |
| title_fullStr | Molecular Deconvolution Platform to Establish Disease Mechanisms by Surveying GPCR Signaling |
| title_full_unstemmed | Molecular Deconvolution Platform to Establish Disease Mechanisms by Surveying GPCR Signaling |
| title_short | Molecular Deconvolution Platform to Establish Disease Mechanisms by Surveying GPCR Signaling |
| title_sort | molecular deconvolution platform to establish disease mechanisms by surveying gpcr signaling |
| url | http://www.sciencedirect.com/science/article/pii/S2211124718310076 |
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