Atrial natriuretic peptide frameshift mutation in familial atrial fibrillation

Abstract

Atrial fibrillation is a common arrhythmia that is hereditary in a small subgroup of patients. In a family with 11 clinically affected members, we mapped an atrial fibrillation locus to chromosome 1p36-p35 and identified a heterozygous frameshift mutation in the gene encoding atrial natriuretic peptide. Circulating chimeric atrial natriuretic peptide (ANP) was detected in high concentration in subjects with the mutation, and shortened atrial action potentials were seen in an isolated heart model, creating a possible substrate for atrial fibrillation. This report implicates perturbation of the atrial natriuretic peptide-cyclic guanosine monophosphate (cGMP) pathway in cardiac electrical instability.

Figure 1. Pedigree of a Family with Hereditary Atrial Fibrillation

Squares indicate male subjects, and circles female subjects. Black denotes affected subjects, and white unaffected subjects; gray indicates that the status of the subject is unknown. A slash through the symbol indicates that the subject is deceased. The gene for atrial natriuretic peptide (NPPA) is located at 1p36-p35. Markers that were tested for this region of chromosome 1 are listed in order from the p-terminal end of the chromosome, with map locations according to the Web site of the National Center for Biotechnology Information (www.ncbi.nlm.nih.gov) and given in megabases and centimorgans. A common c.454C→T polymorphism in exon 3 of wild-type NPPA is included, along with the NPPA mutation (NPPA mut). The haplotypes for these markers are shown in columns beneath family members who underwent genetic evaluation; the disease-associated haplotypes are boxed. Two subjects (III-7 and III-9) inherited portions of the disease haplotype, but not the disease gene, as a result of recombination events.

Figure 2. Radioimmunoassay Analysis Showing the Presence of Mutant ANP in Plasma from Heterozygotes for the NPPA Mutation

A radioimmunoassay with polyclonal antibodies against wild-type atrial natriuretic peptide (ANP), mutant ANP (mANP), and B-type natriuretic peptide (BNP) shows levels of circulating mANP that are 5 to 10 times higher than the levels of ANP in two family members with the NPPA mutation (in Subject III-2 during chronic atrial fibrillation and in Subject III-6 during normal sinus rhythm). In the affected subjects, plasma ANP and BNP levels are normal. Low-level cross-reactivity of the polyclonal anti-mANP antibody was observed in samples from unaffected subject (Subject III-5) and in five control subjects (three female [F] and two male [M]).

Figure 3. Electrophysiological Effects of Circulating Mutant ANP in a Rat Isolated Whole-Heart Model

In Panel A, a representative monophasic action potential (MAP) is shown at baseline and after a 40-minute perfusion with 100 nM of wild-type atrial natriuretic peptide (ANP). MAP duration at 90% repolarization (MAPD₉₀) was not significantly changed by ANP. In Panel B, a representative MAP after a 40-minute perfusion with the mutant form of ANP (mANP) shows a shortening of MAPD₉₀ from 47 to 41 msec. In Panel C, mANP (N = 8 hearts) and wild-type ANP (N = 10 hearts) perfusion for 40 minutes shows a significant decrease in MAPD₉₀ for mANP as compared with the baseline value (9±2 msec, P = 0.005) but not for wild-type ANP (0.7±1.7 msec, P = 0.87). The difference in the change in MAPD₉₀ between mANP and wild-type ANP was also significant (P = 0.008). In Panel D, mANP (N = 7 hearts) and wild-type ANP (N = 6 hearts) perfusion for 40 minutes resulted in a trend toward a reduction in the effective refractory period (ERP), as compared with the baseline value, for mANP (7.1±2.4 msec, P = 0.08) but not for wild-type ANP (P = 0.43). The difference in the change in ERP between mANP and wild-type ANP was significant (P = 0.03). The T bars denote standard errors.