New Insight into Pathogenic Variant p.L275P on the Structure and Function of Steroidogenic Acute Regulatory Protein...

Lipoid congenital adrenal hyperplasia (LCAH) is the lethal form of steroid biosynthesis defects because of mutations in the steroidogenic acute regulatory (STAR) gene. There are two distinct clinical forms including classical and nonclassical without any reliable genotype-phenotype correlation, and investigation of more cases may provide valuable insights.

Ten Iranian families affected by LCAH were selected for genetic linkage analysis. The STAR gene was sequenced in the linked families, and using multiple in silico tools and ACMG guidelines, the pathogenicity of candidate variants was assessed. Also, the structural effects of the identified variant on the STAR behavior were evaluated using molecular docking and molecular dynamics (MD) simulation.

Data analysis revealed a pathogenic variant, c.824T>C, (p.L275P), in the STAR gene in the Iranian population for the first time. Furthermore, molecular docking and MD simulation revealed that the c.824T>C variant results in a decrease in total flexibility and secondary structure, an increase in H-bonds and changed fluctuations in some residues.

MD simulation provides the key structural and structural insights of the p.L275P -mediated conformational changes in STAR.