Supplementary Material for: Mutations in STARD8 (DLC3) may cause 46,XY gonadal dysgenesis

Introduction: 46,XY gonadal dysgenesis is a condition that is characterised by undeveloped testes in individuals with a male karyotype. Mutations in many genes that underlie this condition have been identified; however, there are still a considerable number of patients with an unknown genetic background. Recently, a mutation in the STARD8 X-linked gene in two sisters with 46,XY gonadal dysgenesis has been reported. It was localised within the START domain, whose homologue in Drosophila is responsible for maintaining testis integrity during its development.
Methods: We analysed the potential pathogenicity of another STARD8 mutation, p.R887C, that was identified in a patient with 46,XY asymmetric gonadal dysgenesis. For this purpose, molecular dynamics simulations were performed.
Results: These simulations revealed the full rearrangement of the p.R887C substitution containing the helix upstream from the START domain, which may cause STARD8 protein dysfunction and contribute to 46,XY gonadal dysgenesis. A comparison of the phenotypes of the three described 46,XY gonadal dysgenesis patients that harbour STARD8 mutations indicated that alterations of this gene can result in a partial or complete gonadal dysgenesis phenotype.
Conclusion: Based on these and previous results, it is reasonable to include STARD8 in gene panels for 46,XY gonadal dysgenesis.

引言：46,XY性腺发育不全（46,XY gonadal dysgenesis）是一类以核型为男性的个体出现睾丸发育不全为特征的疾病。目前已鉴定出多个与该疾病发病相关的基因，但仍有相当数量的患者其遗传病因尚未明确。近期有研究报道，在两例罹患46,XY性腺发育不全的姐妹体内发现了X连锁STARD8基因的突变，该突变位点定位于START结构域（START domain），而果蝇（Drosophila）中该结构域的同源蛋白负责维持睾丸发育过程中的结构完整性。
方法：我们对一例确诊为46,XY不对称性腺发育不全的患者体内检出的另一处STARD8突变p.R887C的潜在致病性进行了分析。为此，我们开展了分子动力学模拟（molecular dynamics simulations）实验。
结果：模拟结果显示，携带p.R887C突变的START结构域上游的螺旋结构发生了完全重排，这可能会导致STARD8蛋白功能异常，进而参与46,XY性腺发育不全的发病过程。通过对已报道的3例携带STARD8突变的46,XY性腺发育不全患者的表型进行比较分析，我们发现该基因的突变可引发部分或完全性性腺发育不全表型。
结论：结合本次及既往研究结果，将STARD8纳入46,XY性腺发育不全的基因检测组合是合理的。