DHH pathogenic variants involved in 46,XY disorders of sex development differentially impact protein self-cleavage and structural conformation

Maëva Elzaiat, Delphine Flatters, Diana Carolina Sierra-Díaz, Berangère Legois, Paul Laissue, Reiner A. Veitia

Research output: Contribution to journalArticlepeer-review

Abstract

In humans, pathogenic variants in the DHH gene underlie cases of 46,XY gonadal dysgenesis. DHH is part of the Hedgehog family of proteins, which require extensive processing, including self-cleavage of the precursor for efficient signalling. In our work, we have assessed the effect of several human DHH pathogenic variants involved in recessive complete or partial gonadal dysgenesis, on protein processing and sub-cellular localization. We found that a subset of variants was unable to perform self-cleavage, which correlated albeit not perfectly with an altered subcellular localization of the resulting proteins. For the processing-proficient variants, we used structural modelling tools and molecular dynamic (MD) simulations to predict the potential impact of the variants on protein conformation and/or interaction with partners. Our study contributes to a better understanding of the molecular mechanisms involved in DHH dysfunction leading to 46,XY disorders of sex development.

Original languageEnglish (US)
JournalHuman Genetics
DOIs
StateAccepted/In press - 2020

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

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