An ALMS1 variant disrupts proximal centriole organization and promotes a myofibroblast-like phenotype that is...

Primary endocardial fibroelastosis (pEFE) is characterized by accumulation of elastin-rich extracellular matrix (ECM) in the left ventricular endocardium in the absence of structural defects, but its pathophysiology remains unclear. We investigated dermal fibroblasts from a pEFE patient (proband) harboring a loss-of-function ALMS1 variant. Compared with control fibroblasts, proband cells displayed a myofibroblast-like phenotype, with increased ECM proteins and markers of fibroblast activation and endothelial-to-mesenchymal transition. Conversely, the thymus cell surface antigen (THY1) was downregulated in the proband fibroblasts, which also exhibited reduced ciliation. STED microscopy revealed ALMS1 as a concave, cap-like structure extending into the proximal end of the centriole lumen in control fibroblasts, while it was fragmented in proband fibroblasts and associated with reduced and disorganized Rootletin and C-NAP1 proteins and abnormal centriole separation. Importantly, soluble THY1 reduced production of matrix proteins and markers of fibroblast activation without effects on centriole organization or ciliation. These findings indicate that ALMS1 dysfunction contributes to pEFE pathology through both abnormal proximal centriole organization and THY1-negative fibroblast activation, implicating THY1 as a potential target for pEFE therapy.