A novel Drosophila ALP/Enigma protein binds to Alpha-actinin to promote sarcomere assembly

Z-discs define sarcomere boundaries and anchor actin filaments in muscle, yet many structural components remain uncharacterized. In this paper, we identify three new members of the Alp/Enigma family in Drosophila, including Uchmaz (CG42319), a PDZ domain-containing protein, that we characterize in detail. We used CRISPR/Cas9 to generate multiple uchmaz knockout alleles, which are viable but result in a flightless phenotype. Mutants exhibit disrupted sarcomere organization in the indirect flight muscles (IFMs), including fragmented and misaligned Z-discs and reduced accumulation of α-Actinin and other Z-disc markers. We find that Uchmaz localizes to the Z-disc, associates with α-Actinin, and is dependent upon α-Actinin for its localization to the Z-disc. These results identify Uchmaz as a component of IFM myofibril architecture required for muscle function. Since a human ortholog of uchmaz, PDLIM2, is associated with severe muscle dysfunction in muscular dystrophies and myofibrillar myopathy, our studies provide insight into conserved mechanisms of Z-disc assembly and its relevance to human muscle disease.