Anti-DHCR7 monoclonal antibody Made to order

Context: Low 25-hydroxycholecalciferol [25(OH) vitamin D] status is known to play an important role in many diseases with focus on bone health. Objective: Based on recently reported genetic determinants of vitamin D insufficiency, we aimed to analyze genetic variants of group-specific component (GC), 7-dehydrocholesterol reductase (DHCR7), and cytochrome P450IIR-1 (CYP2R1) for association with vitamin D levels, bone mineral density (BMD), and bone fractures. Design: We conducted a cross-sectional BMD and fracture study and a prospective cohort study. Setting: The cross-sectional study comprised participants of a BMD screening study, and the prospective cohort study comprised nursing home subjects. Patients: The cross-sectional study included 342 subjects (mean age, 55.3 +/- 12.0 yr), and the prospective study included 1093 subjects (mean age, 84.0 +/- 6.0 yr). Interventions: Patients were stratified by GC, DHCR7, and CYP2R1 genotypes. For each gene, the allele associated with lower 25(OH) vitamin D levels was designated as "risk allele." The potential role of these risk alleles in fracture risk was analyzed by logistic regression analysis including age and sex as confounders. Main Outcome Measures: We measured BMD and fractures. Results: GC genotypes were significantly associated with lower mean 25(OH) vitamin D levels in both cohorts (P = 0.001 and P = 0.048, respectively). There was no significant association of BMD with any of the genotypes. None of the alleles was associated with past fractures, whereas the DHCR7 G-allele was significantly associated with prospective fractures (odds ratio, 0.68; 95% confidence interval, 0.51-0.92; P = 0.011). Conclusions: The DHCR7 gene polymorphism may be a predictor for fracture risk. (J Clin Endocrinol Metab 97: E1234-E1240, 2012)

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.