A Zebrafish Model for a Human Myopathy Associated with Mutation of the Unconventional Myosin MYO18B
Genetics Society of America
Copyright © 2017 by the Genetics Society of America
Reason for embargo
Under indefinite embargo due to publisher policy.
Myosin 18B is an unconventional myosin that has been implicated in tumor progression in humans. In addition, loss-of-function mutations of the MYO18B gene have recently been identified in several patients exhibiting symptoms of nemaline myopathy. In mouse, mutation of Myo18B results in early developmental arrest associated with cardiomyopathy, precluding analysis of its effects on skeletal muscle development. The zebrafish, frozen (fro) mutant was identified as one of a group of immotile mutants in the 1996 Tübingen genetic screen. Mutant embryos display a loss of birefringency in their skeletal muscle, indicative of disrupted sarcomeric organization. Using meiotic mapping, we localized the fro locus to the previously unannotated zebrafish myo18b gene, the product of which shares close to 50% identity with its human ortholog. Transcription of myo18b is restricted to fast-twitch myocytes in the zebrafish embryo; consistent with this, fro mutant embryos exhibit defects specifically in their fast-twitch skeletal muscles. We show that sarcomeric assembly is blocked at an early stage in fro mutants, leading to the disorganized accumulation of actin, myosin, and α-actinin and a complete loss of myofibrillar organization in fast-twitch muscles.
This research project was initially funded by a UK Medical Research Council (MRC) Programme grant (G0100151) and subsequently by core support from the IMCB, the Lee Kong Chian School of Medicine (Nanyang Technological University), and the Living Systems Institute (University of Exeter). P.W.I. gratefully acknowledges the support of the Toh Kian Chui foundation.
This is the final version of the article. Available from Genetics Society of America via the DOI in this record.
Vol. 205 (2), pp. 725 - 735
Place of publication