ClinVar

In 6 patients with dilated cardiomyopathy (CMD1CC; 613122), Hassel et al. (2009) identified heterozygosity for a 3-bp deletion in the NEXN gene, resulting loss of a conserved gly650 residue (G650del). The deletion was not found in 1,251 age-, gender-, ethnicity- and geography-matched controls. One proband had a mildly affected brother who carried the deletion and an asymptomatic 33-year-old daughter, who declined further evaluation. Two probands had fathers who did not carry the deletion, and both obligate-carrier mothers had died of cardiac failure; 1 of the 2 probands also had 2 brothers who had died of cardiac failure. All G650del carriers shared an identical haplotype over a large genomic region surrounding the NEXN gene, suggesting a founder effect. Ultrastructural analysis of myocardial biopsy tissue from a G650del patient showed disruption of sarcomeric units with detached and blurry Z discs, similar to that seen in NEXN-deficient zebrafish. Ectopic expression of G650-deleted nexilin in zebrafish resulted in dilated cardiomyopathy, with markedly reduced systolic function and Z disc disruption. Injection of an equal amount of wildtype nexilin had no effect on cardiac function or ultrastructure, indicating a dominant-negative effect of the mutant nexilin.