ArticleCell2024
Pervasive mislocalization of pathogenic coding variants underlying human disorders.
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Article in Cell, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers.
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50 citing papers in PubMed.
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- A comprehensive benchmark of sequence-based subcellular localization predictors for human proteins.Nature methods · 2026Article
- Subcellular localization as a driver of protein function.Nature reviews. Molecular cell biology · 2026Review
- Image-based, pooled phenotyping reveals multidimensional, disease-specific variant effects.Cell · 2026Article
- Cell shapes decode molecular phenotypes in image-based spatial proteomics.Cell systems · 2026Article
- Membrane Protein Insertion in Cells: Principles, Pathways, and Quality Control.Chemical reviews · 2026Review
- Variants in human CD48 lead to impaired T cell immunity and increased inflammation.The Journal of clinical investigation · 2026Article
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- Single-Cell Protein Assays in Context: From 2D to 3D and In Situ Analysis.Annual review of analytical chemistry (Palo Alto, Calif.) · 2026Review
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- Proteoform medicine: characterizing and targeting protein forms in human disease.Nature reviews. Genetics · 2026Review
- ATP13A2 restrains macrophage NLRP3 inflammasome activation to repress neurodegeneration via modulating mitochondrial homeostasis.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
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Authors and funding
29 authors.
Jessica LacosteDonnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
Marzieh HaghighiBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Shahan HaiderDonnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
Chloe RenoDonnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
Zhen-Yuan LinLunenfeld-Tanenbaum Research Institute, Sinai Health, Toronto, ON, Canada.
Dmitri SegalDonnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
Wesley Wei QianDepartment of Computer Science, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
Xueting XiongDonnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
Tanisha TeelucksinghDonnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
Esteban MigliettaBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Hamdah Shafqat-AbbasiBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Pearl V RyderBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Rebecca SenftBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Beth A CiminiBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Ryan R MurrayCenter for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA, USA; Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
Chantal NyirakananiCenter for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA, USA; Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
Tong HaoCenter for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA, USA; Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
Gregory G McClainCenter for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA, USA; Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
Frederick P RothDonnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Lunenfeld-Tanenbaum Research Institute, Sinai Health, Toronto, ON, Canada; Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Michael A CalderwoodCenter for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA, USA; Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
David E HillCenter for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA, USA; Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
Marc VidalCenter for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA, USA; Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
S Stephen YiLivestrong Cancer Institutes, Department of Oncology, Dell Medical School, The University of Texas at Austin, Austin, TX, USA; Oden Institute for Computational Engineering and Sciences (ICES), The University of Texas at Austin, Austin, TX, USA; Department of Biomedical Engineering, Cockrell School of Engineering, The University of Texas at Austin, Austin, TX, USA; Interdisciplinary Life Sciences Graduate Programs (ILSGP), College of Natural Sciences, The University of Texas at Austin, Austin, TX, USA.
Nidhi SahniDepartment of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Quantitative and Computational Biosciences Program, Baylor College of Medicine, Houston, TX, USA.
Jian PengDepartment of Computer Science, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
Anne-Claude GingrasDepartment of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Lunenfeld-Tanenbaum Research Institute, Sinai Health, Toronto, ON, Canada.
Shantanu SinghBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Anne E CarpenterBroad Institute of Harvard and MIT, Cambridge, MA, USA. Electronic address: anne@broadinstitute.org.
Mikko TaipaleDonnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada. Electronic address: mikko.taipale@utoronto.ca.
Funding
Technology to understand genetic variant effects in contextRM1HG010461 · NHGRI · UNIVERSITY OF WASHINGTON · PI Douglas M Fowler, Bruce Colston Trapnell · 2019 to 2026
$18.9MMolecular phenotyping of ~100,000 coding variants across Mendelian disease genesUM1HG011989 · NHGRI · DANA-FARBER CANCER INST · PI Marc Vidal · 2021 to 2026
$9.9MExtracting rich information from biological imagesR35GM122547 · NIGMS · BROAD INSTITUTE, INC. · PI Anne E. Carpenter · 2017 to 2026
$6.2MNetwork-based Framework to Decode Novel Gain-of-Function Mutations and their Mechanistic Roles in General Human DiseasesR35GM133658 · NIGMS · UNIVERSITY OF TEXAS AT AUSTIN · PI S. Stephen Yi · 2019 to 2026
$2.6MDeciphering Functional Consequences of Specific and Combinatorial Mutations in Protein Interaction NetworksR35GM137836 · NIGMS · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI SAHNI, NIDHI · 2020 to 2023
$1.8MNHGRI NIH HHS RM1 HG010461NHGRI NIH HHS UM1 HG011989NIGMS NIH HHS R35 GM122547NIGMS NIH HHS R35 GM133658NIGMS NIH HHS R35 GM137836
Abstract
Widespread sequencing has yielded thousands of missense variants predicted or confirmed as disease causing. This creates a new bottleneck: determining the functional impact of each variant-typically a painstaking, customized process undertaken one or a few genes and variants at a time. Here, we established a high-throughput imaging platform to assay the impact of coding variation on protein localization, evaluating 3,448 missense variants of over 1,000 genes and phenotypes. We discovered that mislocalization is a common consequence of coding variation, affecting about one-sixth of all pathogenic missense variants, all cellular compartments, and recessive and dominant disorders alike. Mislocalization is primarily driven by effects on protein stability and membrane insertion rather than disruptions of trafficking signals or specific interactions. Furthermore, mislocalization patterns help explain pleiotropy and disease severity and provide insights on variants of uncertain significance. Our publicly available resource extends our understanding of coding variation in human diseases.
Indexed as
Mutation, MissenseHumansPhenotypeProtein StabilityProtein Transport
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