Aortic aneurysm, familial thoracic 5 / 3 (AAT5 / AAT3)

Aortic aneurysm, familial thoracic

Aortic aneurysm, familial thoracic (AAT) 3 (AAT3; MIM 610380), AAT4 (MIM 132900), AAT5 (MIM 608976), AAT6 (MIM 611788) and AAT7 (MIM 613780) are dominantly inherited disorders.

AAT5 and AAT3 have been linked to mutations in the transforming growth factor ß receptor type I and II genes (TGFBR1 and TGFBR2). Patients may have aneurysms of the aorta and other arteries. TGFBR2 mutations are currently estimated to be responsible for 5% of familial thoracic aortic aneurysms and dissections (TAAD).

AAT4, thoracic aortic aneurysm and/or dissection with patent ductus arteriosus is caused by mutations in the myosin heavy chain 11 gene (MYH11). It is important to note that not all individuals with myosin heavy chain mutations appear to have dilated aortas. These individuals, though asymptomatic, display a low aortic compliance and distensibility due to a decrease in the elasticity of the aortic wall.

AAT6 is caused by mutations in the ACTA2 gene, which codes for smooth muscle alpha actin. ACTA2 mutations have been identified in several families to date. Mutations in ACTA2 are estimated to be responsible for 14% of familial thoracic aortic aneurysms. Associated findings in AAT6 caused by ACTA2 mutations may include livedo reticularis, a bicuspid aortic valve, iris flocculi and patent ductus arteriosus.

AAT7 is caused by mutations in the MYLK gene. The product of this gene, myosin light chain kinase, phosphorylates the 20 kDa regulatory light chain of smooth and nonmuscle myosin II. Phosphorylation of this molecule is critical for the initiation of smooth muscle contraction.