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.
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We warmly thank Dr. S. Caburet for help with variant reclassification.
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This work was supported by the University Paris Diderot, by the Centre National de la Recherche Scientifique.
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ME, RAV and PL designed research; ME, DF, DCS-D and BL performed research; ME, DF, DCS-D and RAV analysed data; and ME, DF, PL and RAV wrote the paper. ME and DF contributed equally to this work. PL and RAV contributed equally to this work.
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Elzaiat, M., Flatters, D., Sierra-Díaz, D.C. et al. DHH pathogenic variants involved in 46,XY disorders of sex development differentially impact protein self-cleavage and structural conformation. Hum Genet 139, 1455–1470 (2020). https://doi.org/10.1007/s00439-020-02189-5
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DOI: https://doi.org/10.1007/s00439-020-02189-5