Pervasive mislocalization of pathogenic coding variants underlying human disorders.

Journal

Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066

Informations de publication

Date de publication:
25 Sep 2024
Historique:
received: 06 09 2023
revised: 22 07 2024
accepted: 04 09 2024
medline: 3 10 2024
pubmed: 3 10 2024
entrez: 1 10 2024
Statut: aheadofprint

Résumé

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.

Identifiants

DOI: 10.1016/j.cell.2024.09.003 PMID: 39353438
pubmed: 39353438
pii: S0092-8674(24)01021-3
doi: 10.1016/j.cell.2024.09.003
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Informations de copyright

Copyright © 2024 Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

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.

Auteurs

Jessica Lacoste (J)

Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.

Marzieh Haghighi (M)

Broad Institute of Harvard and MIT, Cambridge, MA, USA.

Shahan Haider (S)

Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.

Chloe Reno (C)

Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.

Zhen-Yuan Lin (ZY)

Lunenfeld-Tanenbaum Research Institute, Sinai Health, Toronto, ON, Canada.

Dmitri Segal (D)

Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.

Wesley Wei Qian (WW)

Department of Computer Science, University of Illinois at Urbana-Champaign, Urbana, IL, USA.

Xueting Xiong (X)

Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.

Tanisha Teelucksingh (T)

Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.

Esteban Miglietta (E)

Broad Institute of Harvard and MIT, Cambridge, MA, USA.

Hamdah Shafqat-Abbasi (H)

Broad Institute of Harvard and MIT, Cambridge, MA, USA.

Pearl V Ryder (PV)

Broad Institute of Harvard and MIT, Cambridge, MA, USA.

Rebecca Senft (R)

Broad Institute of Harvard and MIT, Cambridge, MA, USA.

Beth A Cimini (BA)

Broad Institute of Harvard and MIT, Cambridge, MA, USA.

Ryan R Murray (RR)

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.

Chantal Nyirakanani (C)

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.

Tong Hao (T)

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.

Gregory G McClain (GG)

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.

Frederick P Roth (FP)

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.

Michael A Calderwood (MA)

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.

David E Hill (DE)

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.

Marc Vidal (M)

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.

S Stephen Yi (SS)

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.

Nidhi Sahni (N)

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.

Jian Peng (J)

Department of Computer Science, University of Illinois at Urbana-Champaign, Urbana, IL, USA.

Anne-Claude Gingras (AC)

Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Lunenfeld-Tanenbaum Research Institute, Sinai Health, Toronto, ON, Canada.

Shantanu Singh (S)

Broad Institute of Harvard and MIT, Cambridge, MA, USA.

Anne E Carpenter (AE)

Broad Institute of Harvard and MIT, Cambridge, MA, USA. Electronic address: anne@broadinstitute.org.

Mikko Taipale (M)

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.

Classifications MeSH