Computational Investigation of the Missense Mutations in DHCR7 Gene Associated with Smith-Lemli-Opitz Syndrome

International Journal of Molecular Sciences

Wenxing Zhang¹  Rebecca Myers²  Yunhui Peng³  Emil Alexov³ 

[1] Department of Chemistry, Clemson University, Clemson, SC 29630, USA;Department of Healthcare Genetics, Clemson University, Clemson, SC 29630, USA;Department of Physics and Astronomy, Clemson University, Clemson, SC 29630, USA;

关键词: Smith-Lemli-Opitz syndrome;    missense mutations;    DHCR7;    binding free energy;    folding free energy;    KNN classification;    molecular dynamics simulation;    MM/PBSA;   

DOI  :  10.3390/ijms19010141

来源: DOAJ

【 摘 要 】

Smith-Lemli-Opitz syndrome (SLOS) is a cholesterol synthesis disorder characterized by physical, mental, and behavioral symptoms. It is caused by mutations in 7-dehydroxycholesterolreductase gene (DHCR7) encoding DHCR7 protein, which is the rate-limiting enzyme in the cholesterol synthesis pathway. Here we demonstrate that pathogenic mutations in DHCR7 protein are located either within the transmembrane region or are near the ligand-binding site, and are highly conserved among species. In contrast, non-pathogenic mutations observed in the general population are located outside the transmembrane region and have different effects on the conformational dynamics of DHCR7. All together, these observations suggest that the non-classified mutation R228Q is pathogenic. Our analyses indicate that pathogenic effects may affect protein stability and dynamics and alter the binding affinity and flexibility of the binding site.

【 授权许可】

Unknown