ClinVar

In affected members of a Caucasian kindred segregating autosomal dominant early-onset lone atrial fibrillation (ATFB6; 602201), Abraham et al. (2010) identified heterozygosity for a c.190A-C transversion in exon 2 of the NPPA gene, resulting in a ser64-to-arg (S64R) substitution at a conserved residue in the proANP peptide. The missense mutation segregated with disease in the family and was not found in Caucasian, Han Chinese, Asian, or African American population controls. Abraham et al. (2010) noted that ANP levels were not significantly different between family members with AF who were mutations carriers and those who were unaffected and did not carry the mutation. Functional analysis in CHO cells demonstrated that coexpression of mutant NPPA with its ancillary subunit KCNE1 (176261) generated a significantly larger current compared to wildtype, which also activated earlier than wildtype currents. The mutant accelerated both activation and deactivation over all voltages. Pretreatment with anantin, a competitive ANP receptor antagonist, completely eliminated current augmentation and acceleration seen with the mutant, indicating that the effect of the S64R fragment on current is mediated by the endogenous ANP receptor.