Biology subjects

Desnick, R. J.

Publications and source records attributed to Desnick, R. J..

2 recordsLinked to original sources

bioRxiv2026

Environment-dependent landscapes of coding variant impacts on coproporphyrinogen oxidase

Hereditary coproporphyria (HCP) -- caused by variants in coproporphyrinogen oxidase (CPOX) -- can be diagnosed via genome sequencing. However, 74% of clinically-reported CPOX missense variants are classified as variants of uncertain significance (VUS) due to lack of evidence. CPOX variant classification is further complicated by environment-dependence: For example, the CPOX variant p.Asn272His (c.814A>C) is classified as benign yet has been associated with HCP-like symptoms in the context of mercury exposure. Here we measured the functional impact of nearly all possible CPOX amino acid substitutions in both the presence and absence of mercury. The resulting CPOX variant effect maps reflect known protein structure and mutational tolerance patterns while also offering new sequence-structure-function insights. Scores from this atlas not only distinguish pathogenic from benign variants but also identify mercury-dependent variant impacts, thus informing our clinical, structural, and functional understanding of CPOX deficiency and illustrating the value of systematic context-dependent multiplexed assays of genetic variant effects.

molecular biology↗

bioRxiv2023

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

Defects in hydroxymethylbilane synthase (HMBS) can cause Acute Intermittent Porphyria (AIP), an acute neurological disease. Although sequencing-based diagnosis can be definitive, ~[1/3] 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 masse selection, 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.

molecular biology↗