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基因的致病变异是46，XY性腺发育不全的原因。DHH是Hedgehog蛋白质家族的一部分，需要大量的加工过程，包括自我切割前体才能有效地发出信号。在我们的工作中，我们评估了几种人类DHH的作用在蛋白质加工和亚细胞定位中涉及隐性完全或部分性腺发育不全的致病变体。我们发现一个变体的子集无法执行自我切割，这与所产生的蛋白质的亚细胞定位改变并不完美相关。对于具有加工能力的变体，我们使用结构建模工具和分子动力学（MD）模拟来预测变体对蛋白质构象和/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导致DHH功能障碍的46，XY性发育障碍的分子机制。