Abstract
The muscular ventricular septum separates the flow of oxygenated and de-oxygenated blood in air-breathing vertebrates. Defects within it, termed muscular ventricular septal defects (VSDs), are common, yet less is known about how they arise than rarer heart defects. Mutations of the cardiac transcription factor NKX2-5 cause cardiac malformations, including muscular VSDs. We describe here a genetic interaction between Nkx2-5 and Sarcospan (Sspn) that affects the risk of muscular VSD in mice. Sspn encodes a protein in the dystrophin-glycoprotein complex. Sspn knockout (SspnKO) mice do not have heart defects, but Nkx2-5+/−/SspnKO mutants have a higher incidence of muscular VSD than Nkx2-5+/− mice. Myofibers in the ventricular septum follow a stereotypical pattern that is disrupted around a muscular VSD. Subendocardial myofibers normally run in parallel along the left ventricular outflow tract, but in the Nkx2-5+/−/SspnKO mutant they commonly deviate into the septum even in the absence of a muscular VSD. Thus, Nkx2-5 and Sspn act in a pathway that affects the alignment of myofibers during the development of the ventricular septum. The malalignment may be a consequence of a defect in the coalescence of trabeculae into the developing ventricular septum, which has been hypothesized to be the mechanistic basis of muscular VSDs.
Highlights
If the conditional knockout mutants above represent extreme examples of how muscular VSDs arise, subtler signs of abnormal trabecular coalescence may be associated with milder mutations of cardiac developmental genes that cause muscular VSD
Sspn is a gene that resides in a chromosome 6 locus that modifies the risk of muscular VSD in Nkx2-5+/− mice[15]
The present data indicate that Sspn is an Nkx[2,3,4,5] modifier gene, we cannot state definitively whether it is the gene that underlies the chromosome 6 locus
Summary
If the conditional knockout mutants above represent extreme examples of how muscular VSDs arise, subtler signs of abnormal trabecular coalescence may be associated with milder mutations of cardiac developmental genes that cause muscular VSD. Mutations of NKX2-5, a cardiac transcription factor, cause pleiotropic congenital heart defects[13,14]. One modifier locus on chromosome 6 for muscular VSDs was previously mapped in a cross between the C57BL/6N and FVB/N inbred strains[15]. The paucity of knowledge regarding how a muscular VSD arises motivated us to evaluate sarcospan, a gene in the locus. Sarcospan (SSPN) is a transmembrane protein in the dystrophin-glycoprotein complex. Sspn is expressed in the heart and skeletal muscle[16,17]. Mutations of dystrophin-glycoprotein complex genes cause muscular dystrophy. The null mutant is obtained at the expected Mendelian frequency[19], so Sspn deficiency alone would not be expected to cause serious congenital heart defects
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