Knock-out of nexilin in mice leads to dilated cardiomyopathy and endomyocardial fibroelastosis

Cardiomyopathy is one of the most common
causes of chronic heart failure worldwide. Mutations in
the gene encoding nexilin (NEXN) occur in patients with
both hypertrophic and dilated cardiomyopathy (DCM);
however, little is known about the pathophysiological
mechanisms and relevance of NEXN to these disorders.
Here, we evaluated the functional role of NEXN using a
constitutive Nexn knock-out (KO) mouse model.
Heterozygous (Het) mice were inter-crossed to produce
wild-type (WT), Het, and homozygous KO mice. At birth,
32, 46, and 22 % of the mice were WT, Het, and KO,
respectively, which is close to the expected Mendelian
ratio. After postnatal day 6, the survival of the Nexn KO
mice decreased dramatically and all of the animals died
by day 8. Phenotypic characterizations of the WT and KO
mice were performed at postnatal days 1, 2, 4, and 6. At
birth, the relative heart weights of the WT and KO mice
were similar; however, at day 4, the relative heart weight
of the KO group was 2.3-fold higher than of the WT
group. In addition, the KO mice developed rapidly progressive
cardiomyopathy with left ventricular dilation and
wall thinning and decreased cardiac function. At day 6,
the KO mice developed a fulminant DCM phenotype
characterized by dilated ventricular chambers and systolic
dysfunction. At this stage, collagen deposits and some
elastin deposits were observed within the left ventricle
cavity, which resembles the features of endomyocardial
fibroelastosis (EFE). Overall, these results further
emphasize the role of NEXN in DCM and suggest a novel
role in EFE.