Pervasive mislocalization of pathogenic coding variants underlying human disorders

Jessica Lacoste¹, Marzieh Haghighi², Shahan Haider¹, Chloe Reno¹, Zhen-Yuan Lin³, Dmitri Segal¹, Wesley Wei Qian⁴, Xueting Xiong¹, Tanisha Teelucksingh¹, Esteban Miglietta², Hamdah Shafqat-Abbasi², Pearl V Ryder², Rebecca Senft², Beth A Cimini², Ryan R Murray⁵, Chantal Nyirakanani⁵, Tong Hao⁵, Gregory G McClain⁵, Frederick P Roth⁶, Michael A Calderwood⁵, David E Hill⁵, Marc Vidal⁵, S Stephen Yi⁷, Nidhi Sahni⁸, Jian Peng⁴, Anne-Claude Gingras⁹, Shantanu Singh², Anne E Carpenter¹⁰, Mikko Taipale¹¹

Affiliations

¹ Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
² Broad Institute of Harvard and MIT, Cambridge, MA, USA.
³ Lunenfeld-Tanenbaum Research Institute, Sinai Health, Toronto, ON, Canada.
⁴ Department of Computer Science, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
⁵ Center 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.
⁶ Donnelly 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.
⁷ Livestrong 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.
⁸ Department 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.
⁹ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Lunenfeld-Tanenbaum Research Institute, Sinai Health, Toronto, ON, Canada.
¹⁰ Broad Institute of Harvard and MIT, Cambridge, MA, USA. Electronic address: anne@broadinstitute.org.
¹¹ Donnelly 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.

PMID: 39353438
PMCID: PMC11568917 (available on 2025-11-14)
DOI: 10.1016/j.cell.2024.09.003

Pervasive mislocalization of pathogenic coding variants underlying human disorders

Jessica Lacoste et al. Cell. 2024.

. 2024 Nov 14;187(23):6725-6741.e13.

doi: 10.1016/j.cell.2024.09.003. Epub 2024 Sep 30.

Authors

Affiliations

¹ Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
² Broad Institute of Harvard and MIT, Cambridge, MA, USA.
³ Lunenfeld-Tanenbaum Research Institute, Sinai Health, Toronto, ON, Canada.
⁴ Department of Computer Science, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
⁵ Center 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.
⁶ Donnelly 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.
⁷ Livestrong 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.
⁸ Department 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.
⁹ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Lunenfeld-Tanenbaum Research Institute, Sinai Health, Toronto, ON, Canada.
¹⁰ Broad Institute of Harvard and MIT, Cambridge, MA, USA. Electronic address: anne@broadinstitute.org.
¹¹ Donnelly 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.

PMID: 39353438
PMCID: PMC11568917 (available on 2025-11-14)
DOI: 10.1016/j.cell.2024.09.003

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.

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Conflict of interest statement

Declaration of interests A.E.C. serves as a scientific advisor for Recursion, Quiver, and SyzOnc, which use image-based profiling for drug discovery, and receives honoraria for occasional talks at pharmaceutical and biotechnology companies. F.P.R. is a scientific advisor and investor in Constantiam Biosciences, which provides tools for clinical variant annotation.

Update of

Pervasive mislocalization of pathogenic coding variants underlying human disorders.
Lacoste J, Haghighi M, Haider S, Lin ZY, Segal D, Reno C, Qian WW, Xiong X, Shafqat-Abbasi H, Ryder PV, Senft R, Cimini BA, Roth FP, Calderwood M, Hill D, Vidal M, Yi SS, Sahni N, Peng J, Gingras AC, Singh S, Carpenter AE, Taipale M. Lacoste J, et al. bioRxiv [Preprint]. 2023 Sep 5:2023.09.05.556368. doi: 10.1101/2023.09.05.556368. bioRxiv. 2023. Update in: Cell. 2024 Nov 14;187(23):6725-6741.e13. doi: 10.1016/j.cell.2024.09.003. PMID: 37732209 Free PMC article. Updated. Preprint.

References

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Pervasive mislocalization of pathogenic coding variants underlying human disorders

Affiliations

Pervasive mislocalization of pathogenic coding variants underlying human disorders

Authors

Affiliations

Abstract

Conflict of interest statement

Update of

References

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