A familial mutation renders atrial natriuretic peptide resistant to proteolytic degradation

Deborah M. Dickey, Andrea R. Yoder, Lincoln R. Potter

Research output: Contribution to journalArticlepeer-review

53 Scopus citations


A heterozygous frameshift mutation-causing a 12-amino acid extension to the C terminus of atrial natriuretic peptide (ANP) was recently genetically linked to patients with familial, atrial-fibrillation (Hodgson-Zingman, D. M., Karst, M. L., Zingman, L. V., Heublein, D. M., Darbar, D., Herron, K. J., Ballew, J. D., de Andrade, M., Burnett, J. C., Jr., and Olson, T. M. (2008) N. Engl. J. Med. 359, 158-165). The frameshift product (fsANP), but not wild-type ANP (wtANP), was elevated in the serum of affected patients, but the molecular basis for the elevated peptide concentrations was not determined. Here, we measured the ability of fsANP to interact with natriuretic: peptide receptors and to be proteolytically degraded. fsANP and wtANP bound and activated human NPR-A and NPR-C similarly, whereas fsANP had a slightly increased efficacy for human NPR-B. Proteolytic susceptibility was addressed with novel bioassays that measure the time required for kidney membranes or purified neutral endopeptidase to abolish ANP-dependent activation of NPR-A. The half-life of fsANP was markedly greater than that of wtANP in both assays. Additional membrane proteolysis studies indicated that wtANP and fsANP are preferentially degraded by neutral endopeptidase and serine peptidases, respectively. These data indicate that the familial ANP mutation associated with atrial fibrillation has only minor effects on natriuretic peptide receptor interactions but markedly modifies peptide proteolysis.

Original languageEnglish (US)
Pages (from-to)19196-19202
Number of pages7
JournalJournal of Biological Chemistry
Issue number29
StatePublished - Jul 17 2009


Dive into the research topics of 'A familial mutation renders atrial natriuretic peptide resistant to proteolytic degradation'. Together they form a unique fingerprint.

Cite this