Characterization of lethal Drosophila melanogaster alpha-actinin mutants

We have partially characterized four Drosophila melanogaster cu-actinin gen e mutants, I(1)2Cb(1), I(1)2Cb(2), I(1)2Cb(4), and I(1)2Cb(5). We demonstra te that in each case the mutation is caused by a chromosomal rearrangement that precludes normal protein synthesis. In the absence of alpha-actinin, f lies complete embryogenesis and develop into flaccid larvae that die within approximately 24 hr These larvae have noticeable muscle dysfunction at hat ching, although they, nevertheless, are capable of escaping from the egg me mbranes and of subsequent crawling movements. During larval development mus cles degenerate, progressively limit ing mobility and ultimately causing de ath. Electron microscopy of mutant muscle fibers reveals that myofibrils ar e grossly disrupted in one day old larvae and that electron-dense structure s reminiscent of those seen in human nemaline myopathies are present throug hout larval life. Our work rigorously demonstrates that a-actinin deficienc ies are the cause of I(1)2Cb muscle defects. We anticipate that the alpha-a ctinin mutants described herein will facilitate in vivo tests of spectrin s uperfamily protein domain functions using a combination of directed mutagen esis and germline transformation.