Molecular Deconvolution Platform to Establish Disease Mechanisms by Surveying GPCR Signaling.

Cell Reports
Ikuo MasuhoKirill A Martemyanov

Abstract

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.

Citations

Jun 25, 2020·The Journal of Biological Chemistry·Hannah M StovekenKirill A Martemyanov
Nov 29, 2020·Journal of Neural Transmission·Aloysius DomingoLaurie J Ozelius
Jan 19, 2021·Movement Disorders : Official Journal of the Movement Disorder Society·Chiara MelisMichelle E Ehrlich
Feb 4, 2021·Cell Reports·Brian S MunteanKirill A Martemyanov
Oct 31, 2020·Proceedings of the National Academy of Sciences of the United States of America·Marc BehrendtJohannes Oberwinkler

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Datasets Mentioned

BETA
AF493893
AF493874
AF501883
GU174434

Methods Mentioned

BETA
GTPase
nucleotide exchange
BRET
pull-down
transfectability
immunoprecipitation
dissection
electrophoresis
X-ray
FRET

Software Mentioned

GraphPad Prism
Coffee
PolyPhen
OMA browser
ANNOVAR
BoxShade
SIFT
MetaLR
REVEL
Clampfit

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