Scientists ID Novel Mutation That Causes Aortic Aneurysms and Acute Aortic Dissection

Ascending thoracic aortic aneurysms can lead to life-threatening acute aortic dissections (TAADs). An example of this is the sudden death of popular actor John Ritter, who died from this problem. Subsequent examination of his brother Tommy showed that he had a dangerously large aortic aneurysm that was treated surgically to reduce his risk (see John Ritter’s father, Tex Ritter, known as the “Singing Cowboy,” had died suddenly while clutching his chest and is thus presumed to have died from the same problem as his son John. It is known that gene mutations that lead to decreased contraction of vascular smooth-muscle cells (SMCs) can cause inherited thoracic aortic aneurysms and aortic dissections. Using exome sequencing of distant relatives affected by thoracic aortic disease, followed by Sanger sequencing of additional probands with familial thoracic aortic disease, a research group presenting their results on Friday, October 25, at the American Society of Human Genetics (ASHG) 2013 annual meeting in Boston, reported identifying the same rare variant (c.530G>A) (p.Arg177Gln) in the gene PRKG1 in four families. This mutation segregated with aortic disease in the four families, with the majority (63%) of affected individuals presenting with acute aortic dissections at relatively young ages (mean 31 years, range 17-51 years). The PKRG1 gene encodes a type I cGMP-dependent protein kinase (PKG-1) that 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 activated even in the absence of cGMP.
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