Absence of heartbeat in the Xenopus tropicalis mutation muzak is caused by a nonsense mutation in cardiac myosin myh6

Anita Abu-Daya,Dan E Wells,Lyle B Zimmerman,Amy K Sater,Timothy J Mohun

doi:10.1016/j.ydbio.2009.09.019

Anita Abu-Daya, Dan E Wells + Show 3 more

Open Access

https://doi.org/10.1016/j.ydbio.2009.09.019

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Abstract

Mechanisms coupling heart function and cardiac morphogenesis can be accessed in lower vertebrate embryos that can survive to swimming tadpole stages on diffused oxygen. Forward genetic screens in Xenopus tropicalis have identified more than 80 mutations affecting diverse developmental processes, including cardiac morphogenesis and function. In the first positional cloning of a mutation in X. tropicalis, we show that non-contractile hearts in muzak (muz) embryos are caused by a premature stop codon in the cardiac myosin heavy chain gene myh6. The mutation deletes the coiled-coil domain responsible for polymerization into thick filaments, severely disrupting the cardiomyocyte cytoskeleton. Despite the lack of contractile activity and absence of a major structural protein, early stages of cardiac morphogenesis including looping and chamber formation are grossly normal. Muz hearts subsequently develop dilated chambers with compressed endocardium and fail to form identifiable cardiac valves and trabeculae.

Highlights

Formation of the heart is highly conserved in vertebrate species
We show that the lack of cardiac contractility in the muzak mutant is caused by a nonsense mutation truncating the cardiac myosin heavy chain gene myh6
The non-contractile heart phenotype is tightly linked to a nonsense mutation in the myh6 gene deleting the coiled-coil tail domain required for aggregation into functional thick filaments

Summary

Introduction

Genes relevant to human cardiac development and disease can be studied in lower vertebrate models whose externally-developing embryos are accessible during heart forming stages and survive for several days on passively-diffused oxygen if cardiac function is compromised experimentally. We show that the lack of cardiac contractility in the muzak mutant is caused by a nonsense mutation truncating the cardiac myosin heavy chain gene myh. We show that the lack of cardiac contractility in the muzak mutant is caused by a nonsense mutation truncating the cardiac myosin heavy chain gene myh6 Despite this defect in a major structural component of sarcomeres resulting in absence of myofibrils and contractility, looping and chamber formation appear surprisingly normal. This report describes the first positional cloning of a mutation in X. tropicalis

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