SMAD3 and aortic aneurysm: Aneurysms osteoarthritis syndrome (AOS) is a familial syndromic form of aortic aneurysm and early-onset OA that is the result of loss-of-function mutations of SMAD3. For example, one familial form involves a truncating mutation that removes the MH2 domain, while another familial form involves missense mutations that result in conformational changes of the SMAD3 protein, disrupting protein trimerization [10, 11].