Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 93, Issue 2, Pages 398-404Publisher
CELL PRESS
DOI: 10.1016/j.ajhg.2013.06.019
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Funding
- Lung Cohorts Sequencing Project [HL-102923]
- Women's Health Initiative Sequencing Project [HL-102924]
- Heart Cohorts Sequencing Project [HL-103010]
- Broad Institute Sequencing Project [HL-102925]
- GenTAC Registry Consortium [HHSN268200648199C, HHSN268201000048C]
- Northwest Genomics Center Sequencing Project [HL-102926]
- Family Studies Project Team
- University of Texas Health Science Center at Houston [RO1 HL62594, P50HL083794-01, P01HL110869-01, UL1 RR024148]
- Vivian L. Smith Foundation
- TexGen Foundation
- Richard T. Pisani funds
- Groupements d'Interet Scientifique Maladies Rares
- PHRC [A0M09093]
- PHRC AOM [10108]
- ANR from the French National Research Agency [BLAN 1129]
- European Union
- [RO1 GM090161]
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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.Arg177G1n 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.
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