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Functional evaluation of GUCY1A3 mutations associated with myocardial infarction risk

Myocardial infarction (MI) is the main complication of coronary artery disease (CAD). Recently, a locus tagging the GUCY1A3 gene has been shown to be genome-wide significantly associated with CAD [1]. GUCY1A3 encodes for the α1-subunit of the soluble guanylyl cyclase (sGC) which consists of α1- and β1-subunits and catalyzes the production of cGMP upon stimulation with nitric oxide (NO). cGMP acts a second messenger that mediates diverse cellular functions, e.g. smooth muscle relaxation and inhibition of platelet aggregation. Using whole-exome sequencing, our group also identified nine rare variants in the coding sequence of GUCY1A3 [2]. Two of these variants were found in two extended families with a high prevalence of premature CAD/MI. Seven further rare variants were found in 252 young MI patients. In this study, we aimed to investigate the functional implication of these rare variants found in CAD/MI patients (Table 1) regarding protein level, dimerization capability and enzymatic activity.

Table 1 Rare variants of sGC α1 subunit found in MI patients:

Two of the investigated α1 variants exhibited significantly decreased protein levels compared to wild type α1. The amount of β1 correlated with those of α1 in all cases. All α1 variants, except for p.Leu163Phefs*24, still dimerized with the β1 subunit, as shown by co-immunoprecipitation. Using radioimmunoassay three of the rare variants demonstrated significantly decreased cGMP amounts at every time point tested (0.5/1/2 min). The activity only in part correlated with the observed protein levels pointing to an effect of the tested variants on enzymatic activity. As we have shown that loss of function-mutations in GUCY1A3 may lead to CAD/MI [2], decreased enzymatic activity might also increase risk. Future studies focus on mRNA abundance and protein degradation to uncover the reason for attenuated activity of the respective variants.


  1. CARDIoGRAMplusC4D Consortium, Deloukas P, Kanoni S, Willenborg, Farrall M, Assimes TL, et al: Large-scale association analysis identifies new risk loci for coronary artery disease. Nat Genet. 2013, 45 (1): 25-33.

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  2. Erdmann J, Stark K, Esslinger UB, Rumpf, Koesling D, de Wit C, et al: Dysfunctional nitric oxide signalling increases risk of myocardial infarction. Nature. 2013, 504 (7480): 432-436. 10.1038/nature12722.

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Correspondence to Jana Wobst.

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Wobst, J., Dang, T.A., Kessler, T. et al. Functional evaluation of GUCY1A3 mutations associated with myocardial infarction risk. BMC Pharmacol Toxicol 16 (Suppl 1), A100 (2015).

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