A novel loss-of-function mutation in NRAP is associated with left ventricular non-compaction cardiomyopathy.

BACKGROUND

The nebulin-related-anchoring protein () gene encodes actin-associated ankyrin. Few studies reported the association of the gene with cardiomyopathy. Thus, the genetic role of this gene in cardiomyopathy remains to be investigated.

METHODS

The clinical data of the rare case of left ventricular non-compaction (LVNC) were collected and analyzed. Whole-exome sequencing (WES) was performed on related family members. Western blot was used to detect the effect of mutation on the protein expression. The effect of the c.259delC variant on myocardial development was further evaluated in a zebrafish model.

RESULTS

A novel homozygous frameshift mutation c.259delC of was found in the proband with LVNC. It was found that c.259delC decreased the expression of by Western blot. In the zebrafish model, the heart development was affected while knocking out the gene, which showed pericardial edema. The pathological manifestations were uneven hypertrophy, disordered arrangement of cardiomyocytes, enlarged intercellular space, and loose muscle fibers. RNA-sequencing (RNA-seq) showed that the expression of genes related to heart development decreased significantly, and the gene mutation could participate in biological processes (BPs) such as myocardial contraction, cell adhesion, myosin coarse filament assembly of striated muscle, myosin complex composition, and muscle α-actin binding.

CONCLUSION

We identified a rare case of LVNC associated with a novel homozygous NRAP frameshift variant. This study further strengthened the evidence linking mutations in the NRAP gene with LVNC, providing a new clue for further study of LVNC. NRAP may be one of the pathogenic genes of cardiomyopathy.