👤 Mikhail Semenov

Hypertrophic cardiomyopathy (HCM) progressing to end-stage heart failure and heart transplantation (HT) is a rare clinical scenario with an insufficiently explored genetic background. In this single-center retrospective cohort study, we aimed to characterize the genetic spectrum, variants of HCM adverse remodeling, and aspects of molecular pathogenesis of this subgroup. The study included 14 patients (9 females), among whom 10 developed a dilated/hypokinetic phenotype and 4 a restrictive phenotype. In 13 patients (93%), at least one pathogenic or likely pathogenic genetic variant was identified. Dilated remodeling/hypokinesis was associated with loss-of-function variants in Show less

Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC). Here we describe another Axin-associated kinase, whose phosphorylation of beta-catenin precedes and is required for subsequent GSK-3 phosphorylation of beta-catenin. This "priming" kinase is casein kinase Ialpha (CKIalpha). Depletion of CKIalpha inhibits beta-catenin phosphorylation and degradation and causes abnormal embryogenesis associated with excessive Wnt/beta-catenin signaling. Our study uncovers distinct roles and steps of beta-catenin phosphorylation, identifies CKIalpha as a component in Wnt/beta-catenin signaling, and has implications to pathogenesis/therapeutics of human cancers and diabetes. Show less