Volume 16 Supplement 1

Abstracts from the 7th International Conference on cGMP Generators, Effectors and Therapeutic Implications

Open Access

Functional evaluation of GUCY1A3 mutations associated with myocardial infarction risk

  • Jana Wobst1Email author,
  • Tan An Dang1,
  • Thorsten Kessler1,
  • Simon von Ameln1,
  • Stephanie Tennstedt2,
  • Christian Hengstenberg1, 3,
  • Jeanette Erdmann2, 4 and
  • Heribert Schunkert1, 3
BMC Pharmacology and Toxicology201516(Suppl 1):A100

https://doi.org/10.1186/2050-6511-16-S1-A100

Published: 2 September 2015

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:

Variant

Identified in

Predicted effect on protein function

  

PolyPhen-2

SIFT

SNAP

p.Leu163Phefs*24

MI family

frameshift

-

-

p.Lys53Glu

252 young MI cases

possibly damaging damaging

tolerated

non-neutral

p.Thr64Ala

252 young MI cases

benign

tolerated

neutral

p.Thr229Met

252 young MI cases

possibly damaging

tolerated

non-neutral

p.Ser478Gly

252 young MI cases

benign

tolerated

neutral

p.Val587Ile

252 young MI cases

benign

tolerated

neutral

p.Gly573Arg

MI family

probably damaging

affect protein function

non-neutral

p.Cys610Tyr

252 young MI cases

probably damaging

tolerated

neutral

p.Ile571Val

252 young MI cases

possibly damaging

affect protein function

neutral

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.

Authors’ Affiliations

(1)
Klinik für Herz-und Kreislauferkrankungen, Deutsches Herzzentrum München, Technische Universtität München
(2)
Institut für Integrative und Experimentelle Genomik, Universität zu Lübeck
(3)
Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK) e.V., partner site Munich Heart Alliance (MHA)
(4)
Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK) e.V., partner site Hamburg/Kiel/Lübeck

References

  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.Google Scholar
  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.View ArticlePubMedGoogle Scholar

Copyright

© Wobst et al. 2015

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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