Aortic aneurysm, familial thoracic (AAT) 3 (AAT3; MIM 610380), AAT4 (MIM 132900), AAT5 (MIM 608967), AAT6 (MIM 611788), AAT7 (MIM 613780), AAT8 (MIM 615436), AAT9 (MIM 616166), SMAD3 related AAT, TGFB2 related AAT and TGFB3 related AAT 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.
AAT8 is caused by a gain of function mutation in the PRKG1 gene, which encodes a cGMP-dependent regulatory protein kinase. An Arg177Gln substitution, which results in constitutive activation of the encoded protein kinase, has been identified in all currently reported patients. This PRKG1 mutation results in early onset thoracic disease as all patients over the age of 18 showed aortic dilation and acute aortic dissection occurred in patients as young as 17. In addition to thoracic aneurysms and dissections, some patients with the PRKG1 mutation also exhibit other vascular abnormalities, including abdominal aortic aneurysms, atrial septal aneurysms, tortuosity of the thoracic aorta, and coronary artery aneurysms and dissections.
AAT9 is caused by mutations in MFAP5. MFAP5 codes for microfibrillar-associated protein 5, a component of fibrillin-containing microfibrils and other microfibril-associated proteins. In addition to AAT, patients with MFAP5 mutations may have additional findings including atrial fibrillation, arachnodactyly, high-arched palate and pectus deformities.
SMAD3 and TGFB2 mutations have also been identified in patients with AAT (SMAD3 related AAT and TGFB2 related AAT). The phenotypes of patients with SMAD3 and TGFB2 mutations are similar. There is also considerable phenotypic overlap with Loeys-Dietz syndrome, type 3 / aneurysms-osteoarthritis syndrome (LDS3 / AOS; MIM 613795) and Loeys-Dietz syndrome, type 4 (LDS4; MIM 614816). SMAD3 mutations are estimated to cause about 2% of AAT cases with or without intracranial or other arterial aneurysms. In two studies, TGFB2 mutations were detected in 1.5% and 25% of sampled familial cases, which had previously tested negative for mutations in other AAT genes.
Mutations in the TGFB3 gene have been reported to cause syndromic aortic aneurysms and dissections (TGFB3 related AAT). It overlaps clinically with Loeys-Dietz, Shprintzen-Goldberg, and Marfan syndromes. The cardiovascular phenotype includes thoracic and/or abdominal aortic aneurysm and dissection, and mitral valve disease. Other common findings include cleft palate, bifid uvula, cervical spine instability, club foot, scoliosis, and skeletal overgrowth.
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