Desmin tail mutation linked to human dilated cardiomyopathy promotes cleavage of the N-terminus and abolishes z-disc localization

Abstract

A missense mutation (Ile 451 to Met) at the tail domain of the muscle specific intermediate filament protein desmin has been suggested to be a genetic cause of dilated cardiomyopathy. Most of the desmin mutations (usually at the central rod domain) have as result the intracytoplasmic accumulation of desmin and other proteins aggregates in muscle cells. These aggregates are a major histological hallmark of desminopathies. Surprisingly most of the desmin tail domain mutants have the ability to form proper filaments on their own, so we hypothesize that filament-forming mutations will critically interfere with the binding of the filaments to z-disc or intercalated disc components, or proteins that are part of muscle-specific signaling cascades.