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

Area of Science:

• Genetics
• Biochemistry
• Molecular Biology

Background:

• Lipoid congenital adrenal hyperplasia (LCAH) is a severe genetic disorder affecting steroid biosynthesis.
• Mutations in the steroidogenic acute regulatory (STAR) gene cause LCAH, but genotype-phenotype correlations remain unclear.
• Investigating more LCAH cases is crucial for understanding disease mechanisms.

Purpose of the Study:

• To identify genetic variants in the STAR gene associated with LCAH in Iranian families.
• To elucidate the structural and functional consequences of identified STAR gene variants.

Main Methods:

• Genetic linkage analysis and STAR gene sequencing were performed on ten Iranian LCAH families.
• Candidate variant pathogenicity was assessed using in silico tools and ACMG guidelines.
• Molecular docking and molecular dynamics (MD) simulations evaluated the structural impact of variants on STAR protein.

Main Results:

• A novel pathogenic variant, c.824T>C (p.L275P), in the STAR gene was identified in the Iranian LCAH population.
• Molecular docking and MD simulations demonstrated that the c.824T>C variant alters STAR protein structure.
• The p.L275P variant leads to reduced flexibility, decreased secondary structure, increased H-bonds, and altered residue fluctuations.

Conclusions:

• The study identified a new pathogenic STAR gene variant contributing to LCAH in Iran.
• MD simulations provided critical insights into the structural changes in STAR protein caused by the p.L275P variant.
• These findings enhance the understanding of LCAH pathogenesis and STAR protein function.