Atp6v1e1b deficiency causes endosomal and mitochondrial defects with a role for transferrin and lipid metabolism in disease pathogenesis of metabolic CL-syndrome

Mutations in subunit V1E1 of the vacuolar H+-ATPase (ATP6V1E1) cause a recently described cutis laxa (CL) syndrome, resembling autosomal recessive cutis laxa (ARCL) type 2A. In addition to a loose redundant skin, facial dysmorphisms, marfanoid habitus, patients are at risk for aortic root dilatation and hypertrophic cardiomyopathy. We investigate the pathogenesis underlying the pleiotropic manifestations in two danio rerio models knock-out (KO) for atp6v1e1b. The zebrafish models faithfully recapitulate the features of ATP6V1E1 related CL. Atp6v1e1b deficiency causes reduced maturation of the endosomal pathway as evidenced by increased protein expression of early endosomal antigen 1 (EEA1). RNA-sequencing revealed significant downregulation of transferrin-a (tfa) and genes involved in lipid metabolism. Mitochondria appear dilated and are dysfunctional with a decreased basal oxygen consumption rate. Lipidomic analysis remarked alterations in phospholipids and sphingolipids compared to wild type controls. Hence, our findings demonstrate that aberrant signaling of the endosomal pathway, leading to disruptions of iron trafficking, and aberrant lipid metabolism are key factors in the pathogenesis of ARCL type 2A.