UMR7592 Institut Jacques Monod, CNRS-Université Paris Diderot, 15 rue Hélène Brion, 75013, Paris, France.
Université de Paris, BFA, UMR 8251, CNRS, ERL U1133, Inserm, 75013, Paris, France.
Hum Genet. 2020 Nov;139(11):1455-1470. doi: 10.1007/s00439-020-02189-5. Epub 2020 Jun 5.
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.
在人类中，DHH 基因的致病性变异导致 46,XY 性腺发育不全。DHH 是 Hedgehog 蛋白家族的一部分，该家族的蛋白需要广泛的加工，包括前体的自我切割，以实现有效的信号传递。在我们的工作中，我们评估了几种涉及隐性完全或部分性腺发育不全的人类 DHH 致病性变异对蛋白加工和亚细胞定位的影响。我们发现，一部分变异无法进行自我切割，这与所产生的蛋白的亚细胞定位改变相关，但并非完全相关。对于具有加工能力的变异，我们使用结构建模工具和分子动力学 (MD) 模拟来预测变异对蛋白构象和/或与伴侣相互作用的潜在影响。我们的研究有助于更好地理解 DHH 功能障碍导致 46,XY 性别发育障碍的分子机制。
