Systematically testing human HMBS missense variants to reveal mechanism and pathogenic variation

Author:

van Loggerenberg WarrenORCID,Sowlati-Hashjin Shahin,Weile JochenORCID,Hamilton Rayna,Chawla Aditya,Gebbia Marinella,Kishore Nishka,Frésard Laure,Mustajoki Sami,Pischik Elena,Pierro Elena Di,Barbaro Michela,Floderus Ylva,Schmitt Caroline,Gouya Laurent,Colavin Alexandre,Nussbaum Robert,Friesema Edith C. H.,Kauppinen Raili,To-Figueras Jordi,Aarsand Aasne K.,Desnick Robert J.,Garton Michael,Roth Frederick P.

Abstract

AbstractDefects in hydroxymethylbilane synthase (HMBS) can cause Acute Intermittent Porphyria (AIP), an acute neurological disease. Although sequencing-based diagnosis can be definitive, ~⅓ of clinical HMBS variants are missense variants, and most clinically-reported HMBS missense variants are designated as “variants of uncertain significance” (VUS). Using saturation mutagenesis,en masseselection, and sequencing, we applied a multiplexed validated assay to both the erythroid-specific and ubiquitous isoforms of HMBS, obtaining confident functional impact scores for >84% of all possible amino-acid substitutions. The resulting variant effect maps generally agreed with biochemical expectation. However, the maps showed variants at the dimerization interface to be unexpectedly well tolerated, and suggested residue roles in active site dynamics that were supported by molecular dynamics simulations. Most importantly, these HMBS variant effect maps can help discriminate pathogenic from benign variants, proactively providing evidence even for yet-to-be-observed clinical missense variants.

Publisher

Cold Spring Harbor Laboratory

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