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  • van Loggerenberg, W (author)

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

  • Article/chapterEnglish2023

Publisher, publication year, extent ...

  • Cold Spring Harbor Laboratory,2023

Numbers

  • LIBRIS-ID:oai:prod.swepub.kib.ki.se:236798224
  • http://kipublications.ki.se/Default.aspx?queryparsed=id:236798224URI
  • https://doi.org/10.1101/2023.02.06.527353DOI

Supplementary language notes

  • Language:English
  • Summary in:English

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  • Subject category:vet swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • Defects 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.

Added entries (persons, corporate bodies, meetings, titles ...)

  • Sowlati-Hashjin, S (author)
  • Weile, J (author)
  • Hamilton, R (author)
  • Chawla, A (author)
  • Gebbia, M (author)
  • Kishore, N (author)
  • Frésard, L (author)
  • Mustajoki, S (author)
  • Pischik, E (author)
  • Di Pierro, E (author)
  • Barbaro, M (author)
  • Floderus, YKarolinska Institutet (author)
  • Schmitt, C (author)
  • Gouya, L (author)
  • Colavin, A (author)
  • Nussbaum, R (author)
  • Friesema, ECH (author)
  • Kauppinen, R (author)
  • To-Figueras, J (author)
  • Aarsand, AK (author)
  • Desnick, RJ (author)
  • Garton, M (author)
  • Roth, FP (author)
  • Karolinska Institutet (creator_code:org_t)

Related titles

  • In:bioRxiv : the preprint server for biology: Cold Spring Harbor Laboratory

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