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.
Translated title of the contribution | Las variantes patogénicas DHH implicadas en los trastornos 46,XY del desarrollo sexual afectan de forma diferencial a la autolimpieza de la proteína y a su conformación estructural |
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Original language | English (US) |
Pages (from-to) | 1455–1470 |
Number of pages | 16 |
Journal | Human Genetics |
Volume | 139 |
DOIs | |
State | Published - Jun 5 2020 |
All Science Journal Classification (ASJC) codes
- Genetics
- Genetics(clinical)