Substitutions at position 263 within the von Willebrand factor type A domain determine the functionality of complement C2 protein.

The complement system is one of the first defense lines protecting from invading pathogens. However, it may turn offensive to the body's own cells and tissues when deregulated by the presence of rare genetic variants that impair physiological regulation and/or provoke abnormal activity of key enzymatic components. Factor B and complement C2 are examples of paralogs engaged in the alternative and classical/lectin complement pathway, respectively. Pathogenic mutations in the von Willebrand factor A domain (vWA) of FB have been known for years. Despite substantial homology between two proteins and the demonstration that certain substitutions in FB translated to C2 result in analogous phenotype, there was a limited number of reports on pathogenic C2 variants in patients. Recently, we studied a cohort of patients suffering from rare kidney diseases and confirmed the existence of two gain-of-function and three loss-of-function mutations within the C2 gene sequences coding for the vWA domain (amino acids 254-452) or nearly located unstructured region (243-253) of C2 protein. Herein, we report the functional consequences of amino acid substitution of glutamine at position 263. The p.Q263G variant resulted in the gain-of-function phenotype, similarly to a homologous mutation p.D279G in FB. Conversely, the p.Q263P variant found in a patient with C3 glomerulopathy resulted in the loss of C2 function. Our results confirm that the N-terminal part of the vWA domain is a hot spot crucial for the complement C2 function.

Erectile Dysfunction in Men Burdened with the Familial Occurrence of Coronary Artery Disease.

Erectile dysfunction (ED) and coronary artery disease (CAD) share common risk factors, some of which have genetic backgrounds, while others may be stimulated by family lifestyle. We investigated the impact of the familial occurrence of CAD on the presence of ED and the presence of classic risk factors for ED in men with CAD. This cross-sectional observational study involved 751 men with CAD who were subjected to cardiac rehabilitation. Overall, 75.63% of the men had ED. CAD was diagnosed in 39.28% of the studied men's relatives. ED was less frequent in the men with familial CAD than in those without (71.53% vs. 78.29%). Similar relations were observed for the presence of CAD in parents (70.43% vs. 78.34%) and the father (69.95% vs. 77.46%). The International Index of Erectile Function 5 score was significantly higher in patients with familial CAD (median (interquartile range); 17 (12-22) vs. 16 (10-21); p = 0.0118), in parents (18 (12-22) vs. 16 (10-20); p = 0.021), and in the father (18 (12-22) vs. 16 (10-21); p = 0.0499). Age and education minimized the effect of familial CAD. Familial CAD increased the incidence of hypertension, dyslipidemia, and smoking but not sedentary lifestyle. Despite the higher prevalence of selected risk factors for ED in men with familial CAD, a higher incidence of ED was not observed.