Evidence map›Paper›PMID 37732209›Full record

ArticlebioRxiv : the preprint server for biology2023

Pervasive mislocalization of pathogenic coding variants underlying human disorders.

Jessica Lacoste, Marzieh Haghighi, Shahan Haider, Zhen-Yuan Lin, Dmitri Segal, Chloe Reno, Wesley Wei Qian, Xueting Xiong, Hamdah Shafqat-Abbasi, Pearl V Ryder and 13 more

Open access · greenAbstract readPreprint
PubMed Full text at PMC Publisher
In one paragraph

Article in bioRxiv : the preprint server for biology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed, 9 citations in OpenAlex.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

23 authors at 7 institutions in 2 countries.

Jessica LacosteDonnelly Centre for Cellular and Biomolecular Research, University of Toronto, Canada.
Marzieh HaghighiBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Shahan HaiderDonnelly Centre for Cellular and Biomolecular Research, University of Toronto, Canada.
Zhen-Yuan LinLunenfeld-Tanenbaum Research Institute, Sinai Health, Toronto, Canada.
Dmitri SegalDonnelly Centre for Cellular and Biomolecular Research, University of Toronto, Canada.
Chloe RenoDonnelly Centre for Cellular and Biomolecular Research, University of Toronto, 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, Canada.
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.
Frederick P RothDonnelly Centre for Cellular and Biomolecular Research, University of Toronto, Canada.
Michael CalderwoodCenter for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA, USA.
David HillCenter for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA, USA.
Marc VidalCenter for Cancer Systems Biology (CCSB), 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.
Nidhi SahniDepartment of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, 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, Canada.
Shantanu SinghBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Anne E CarpenterBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Mikko TaipaleDonnelly Centre for Cellular and Biomolecular Research, University of Toronto, Canada.
University of Toronto · CABroad Institute · USHarvard University · USUniversity of Illinois Urbana-Champaign · USLivestrong Foundation · USLunenfeld-Tanenbaum Research Institute · CAThe University of Texas MD Anderson Cancer Center · US

Funding

Molecular phenotyping of ~100,000 coding variants across Mendelian disease genesUM1HG011989 · NHGRI · DANA-FARBER CANCER INST · PI Marc Vidal · 2021 to 2026
$9.9M
Extracting rich information from biological imagesR35GM122547 · NIGMS · BROAD INSTITUTE, INC. · PI Anne E. Carpenter · 2017 to 2026
$6.2M
Network-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
$2.6M
Deciphering 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
$1.8M
NHGRI NIH HHS UM1 HG011989NIGMS NIH HHS R35 GM122547NIGMS NIH HHS R35 GM133658NIGMS NIH HHS R35 GM137836
6 · The paper itself

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 - largely a painstaking, customized process undertaken one or a few genes or variants at a time. Here, we established a high-throughput imaging platform to assay the impact of coding variation on protein localization, evaluating 3,547 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 unknown significance. Our publicly available resource will likely accelerate the understanding of coding variation in human diseases.

Identifiers

PMID37732209
PMCPMC10508771
OpenAlexW4386478954

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC-ND
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.