Genetic Mutation Linked to Thoracic Aortic Disease

Gene mutations that lead to decreased contraction of vascular smooth-muscle cells (SMCs) can cause inherited thoracic aortic aneurysms and dissections.

A multi-institutional team led by scientists at the University of Texas Health Science Center (Houston, TX, USA) performed 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.

The variant is in the gene known as protein kinase, cyclic guanosine monophosphate (cGMP)-dependent, type I (PRKG1) makes a protein called cGMP-dependent kinase, type I. The PRKG1 mutation alters the function of the protein and causes the muscle cells in the wall of the aorta to respond incorrectly to pulsatile blood flow from the heart, and the change in this one protein ultimately causes thoracic aortic aneurysm and acute aortic dissection.

Scientists have now discovered nine different genes linked to familial thoracic aortic disease. Family members who have inherited the mutated gene will need to be monitored by a cardiologist, undergo regular imaging of the aorta, and take medications to control high blood pressure and reduce the stress on the aorta. Thoracic aortic aneurysms and dissections are familial in up to 20% of all cases. 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.

Of the individuals in the study who have the mutation, 63% had acute aortic dissections and 37 % have aortic root enlargement. Of the 19 family members with dissections, five had a diagnosis of hypertension and five had evidence of damage associated with hypertension such as left ventricular hypertrophy or chronic small vessel cerebrovascular disease.

Dianna Milewicz, MD, PhD, who led the study said, “What is unique about this finding is that we identified four unrelated families from around the world and of different ethnicities who have the exact same genetic mutation, which is one altered base pair out of the three billion base pairs that make up our DNA. The protein is normally regulated but this mutation causes the protein to be always active, almost like the brakes have gone out on a car and it cannot stop." The study was published on August 8, 2013, in the American Journal of Human Genetics.

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University of Texas Health Science Center