ArticleNature structural & molecular biology2025
Multiplex and multimodal mapping of variant effects in secreted proteins via MultiSTEP.
Article in Nature structural & molecular biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed.
- Why variant effect predictors and multiplexed assays agree and disagree.Nature communications · 2026Article
- BCAR: a fast and indel-tolerant barcode-sequence mapper.Bioinformatics (Oxford, England) · 2026Article
- Combining multiplexed functional data to improve variant classification.Genome medicine · 2026Article
- An integrated, scaled approach to resolve TSC2 variants of uncertain significance.Nature communications · 2026Article
- How far can you go? Extrapolating values of catalytic activity from known protein landscapes in natural and directed evolution.Chemical Society reviews · 2026Review
- Massively parallel functional genomic assays in endocrinology: from promise to delivery.Journal of molecular endocrinology · 2026Review
- HaloTag-based approach to quantify subcellular localization of TRPV3 channels.Biophysical journal · 2026Article
- BCAR: A fast and general barcode-sequence mapper for correcting sequencing errors.bioRxiv : the preprint server for biology · 2026Article
- Determining the intra-residue correlation of missense variant impact using MAVE scores: implications for the ACMG/AMP PM5 criterion for DNA variant classification.Genome medicine · 2026Article
- Creating an atlas of variant effects to resolve variants of uncertain significance and guide cardiovascular medicine.Nature reviews. Cardiology · 2026Review
- A scalable approach to resolving variants of uncertain significance.bioRxiv : the preprint server for biology · 2026Article
- An integrated, scaled approach to resolve TSC2 variants of uncertain significance.bioRxiv : the preprint server for biology · 2026Article
- Engineering mammalian protein secretion: Toward the convergence of high-throughput biology and computational methods.Cell systems · 2025Review
- MaveMD: A functional data resource for genomic medicine.medRxiv : the preprint server for health sciences · 2025Article
- "An integrated multitool analysis contributes elements to interpreting unclassified factor IX missense variants associated with hemophilia B": comment from Lee et al.Journal of thrombosis and haemostasis : JTH · 2025Article
- Article
- Review
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- Systematic genetic characterization of the human PKR kinase domain highlights its functional malleability to escape a poxvirus substrate mimic.bioRxiv : the preprint server for biology · 2024Article
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15 authors.
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Abstract
Despite widespread advances in DNA sequencing, the functional consequences of most genetic variants remain poorly understood. Multiplexed assays of variant effect can measure the function of variants at scale but cannot readily be applied to the ~10% of human genes encoding secreted proteins. Here we develop a flexible, scalable human cell surface display method, multiplexed surface tethering of extracellular proteins (MultiSTEP), to study the consequences of missense variation in coagulation factor IX (FIX), a serine protease in which genetic variation can cause hemophilia B. We combine MultiSTEP with a panel of antibodies to detect FIX secretion and post-translational modification (PTM), measuring 44,816 variant effects for 436 synonymous variants and 8,528 of the 8,759 possible F9 missense variants. Almost half of missense variants impact secretion, PTM or both. We also identify functional constraints on secretion within the signal peptide and for nearly all gain or loss of cysteine variants. Secretion scores correlate strongly with FIX levels in hemophilia B and reveal that loss-of-secretion variants are more often associated with severe disease. Integration of the secretion and PTM scores enables reclassification of 63.1% of F9 variants of uncertain significance in the My Life, Our Future hemophilia genotyping project. Lastly, we show that MultiSTEP can be applied to other secreted proteins, thus demonstrating that MultiSTEP is a multiplexed, multimodal and generalizable method for systematically assessing variant effects in secreted proteins at scale.
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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.