PMC4761329_01
A rare p.R366H mutation in CYP21A2 in a kindred with congenital adrenal hyperplasia. An established nomogram showing basal and stimulated serum 17-hydroxyprogesterone levels, with measured values in proband (p), and his male siblings (a and b) indicative of non-classical congenital adrenal hyperplasia (A). Family pedigree shows CYP21A2 genotypes, as determined by Sanger sequencing (B). Mapping of the newly discovered p.R366H mutation to our humanized model of wild-type CYP21A2 (C). By forming a salt-bridge with D111, R366 (beta4 sheet) holds the B'-helix in position that is implicated in gating (highlighted in blue). The p.R366H mutation results in the loss of one of two hydrogen bonds (dashed lines), thus weakening, but not abolishing the ion-pair interaction. In contrast, a loss of both hydrogen bonds in the p.R366C mutation disrupts enzyme stability to cause salt wasting disease.
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F1
The R366 residue (beta4 sheet) normally forms a salt-bridge with D111 (B'-C loop); this ion-pair interaction holds the B'-helix in position allowing for appropriate gating of binding sites (Fig. 1C).