Recurrent gain-of-function mutation in PRKG1 causes thoracic aortic aneurysms and acute aortic dissections.
Publication/Presentation Date
8-8-2013
Abstract
Gene mutations that lead to decreased contraction of vascular smooth-muscle cells (SMCs) can cause inherited thoracic aortic aneurysms and dissections. Exome sequencing of distant relatives affected by thoracic aortic disease and subsequent Sanger sequencing of additional probands with familial thoracic aortic disease identified the same rare variant, PRKG1 c.530G>A (p.Arg177Gln), in four families. This mutation segregated with aortic disease in these families with a combined two-point LOD score of 7.88. The majority of affected individuals presented with acute aortic dissections (63%) at relatively young ages (mean 31 years, range 17-51 years). PRKG1 encodes type I cGMP-dependent protein kinase (PKG-1), which is activated upon binding of cGMP and controls SMC relaxation. Although the p.Arg177Gln alteration disrupts binding to the high-affinity cGMP binding site within the regulatory domain, the altered PKG-1 is constitutively active even in the absence of cGMP. The increased PKG-1 activity leads to decreased phosphorylation of the myosin regulatory light chain in fibroblasts and is predicted to cause decreased contraction of vascular SMCs. Thus, identification of a gain-of-function mutation in PRKG1 as a cause of thoracic aortic disease provides further evidence that proper SMC contractile function is critical for maintaining the integrity of the thoracic aorta throughout a lifetime.
Volume
93
Issue
2
First Page
398
Last Page
404
ISSN
1537-6605
Published In/Presented At
Guo, D. C., Regalado, E., Casteel, D. E., Santos-Cortez, R. L., Gong, L., Kim, J. J., Dyack, S., Horne, S. G., Chang, G., Jondeau, G., Boileau, C., Coselli, J. S., Li, Z., Leal, S. M., Shendure, J., Rieder, M. J., Bamshad, M. J., Nickerson, D. A., GenTAC Registry Consortium, National Heart, Lung, and Blood Institute Grand Opportunity Exome Sequencing Project, … Milewicz, D. M. (2013). Recurrent gain-of-function mutation in PRKG1 causes thoracic aortic aneurysms and acute aortic dissections. American journal of human genetics, 93(2), 398–404. https://doi.org/10.1016/j.ajhg.2013.06.019
Disciplines
Medicine and Health Sciences
PubMedID
23910461
Department(s)
Department of Surgery
Document Type
Article