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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 http://www.johnritterfoundation.org). 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. The increased PKG-1 activity leads to decreased phosphorylation of the myosin light chain in fibroblasts and is predicted to cause decreased contraction of vascular SMCs. The researchers said that the 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. The group’s findings were presented by Dhong-chuan Guo, Ph.D., Assistant Professor in the Medical Genetics Core Lab of the University of Texas Medical School at Houston at the ASHG meeting. The results were also previously reported in the American Journal of Human Genetics in August 2013, and Dianna M. Milewicz, M.D., Ph.D., Professor and Vice Chairperson of the Department of Internal Medicine at the University of Texas Medical School at Houston, was the senior author of that paper. Dr. Guo was the first author. This BioQuick report is based on an ASHG abstract of the work and the published article in the American Journal of Human Genetics, together with information provided by Dr. Guo and Dr. Milewicz at an ASHG press briefing. The ASHG is the primary professional membership organization for nearly 8,000 human genetics specialists worldwide. The ASHG Annual Meeting is the world's largest gathering of human genetics professionals and a forum for renowned experts in the field. Approximately 6,700 genetics professionals attended the 2013 annual meeting in Boston, which ended on Saturday, October 26. For more information about the ASHG, visit: http://www.ashg.org. [AJHG journal abstract] [John Ritter Foundation] [ASHG Annual Meeting 2013]