Mutations in STARD8 (DLC3) May Cause 46,XY Gonadal Dysgenesis

Abstract

<b><i>Introduction:</i></b> 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 <i>STARD8</i> X-linked gene in two sisters with 46,XY gonadal dysgenesis has been reported. It was localised within the START domain, whose homologue in <i>Drosophila</i> is responsible for maintaining testes integrity during their development. <b><i>Methods:</i></b> We analysed the potential pathogenicity of another <i>STARD8</i> mutation, p.R887C, that was identified in a patient with 46,XY asymmetric gonadal dysgenesis. For this purpose, molecular dynamics simulations were performed. <b><i>Results:</i></b> These simulations revealed the full rearrangement of the helix containing the p.R887C substitution 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 <i>STARD8</i> mutations indicated that alterations of this gene can result in a partial or complete gonadal dysgenesis phenotype. <b><i>Conclusion:</i></b> Based on these and previous results, it is reasonable to include <i>STARD8</i> in gene panels for 46,XY gonadal dysgenesis.