The p.Arg490Trp variant of PKP2 was identified in two unrelated ARVC probands and absent from 470 controls. In silico analysis suggests that PKP2 exon 6 is an Alu-derived sequence with very low expression level. Transcriptional and Western blot analysis confirmed that the exon 6 missing PKP2a was the only clearly detectable isoform in all heart samples (four controls and a proband). Moreover, in the proband's heart sample, the variant was not associated with aberrant exon 6 splicing or mutant mRNA down-regulation. Finally, we identified in this proband a heterozygous missense variant (p.Glu2343Lys) in the desmoplakin gene likely to be the disease-causing mutation.
We demonstrated that only PKP2a is significantly expressed in the heart. Our results strongly suggest that the p.Arg490Trp mutation and other variants located in PKP2 exon 6 can not be considered as disease-causing mutations and therefore that PKP2 exon 6 screening is useless in routine ARVC molecular diagnosis. These results have important consequences for the interpretation of PKP2 mutation screening and subsequent genetic counseling.