We review current knowledge regarding naturally occurring mutations in the human apolipoprotein A-I (APOA1) gene with a focus on their clinical complications as well as their exploitation for the elucidation of structure–function–(disease) relationships and therapy. Bi-allelic loss-of-function mutations in APOA1 cause HDL deficiency and, in the majority of patients, premature atherosclerotic cardiovascular disease (ASCVD) and corneal opacities. Heterozygous HDL-cholesterol decreasing mutations in APOA1 were associated with increased risk of ASCVD in several but not all studies. Some missense mutations in APOA1 cause familial amyloidosis. Structure–function-reationships underlying the formation of amyloid as well as the manifestion of amyloidosis in specific tissues are better understood. Lessons may also be learnt from the progress in the treatment of amyloidoses induced by transthyretin variants. Infusion of reconstituted HDL (rHDL) containing apoA-I (Milano) did not cause regression of atherosclerosis in coronary arteries of patients with acute coronary syndrome. However, animal experiments indicate that rHDL with apoA-I (Milano) or apoA-I mimetic peptides may be useful for the treatment of heart failure of inflammatory bowel disease. Specific mutations in APOA1 are the cause of premature ASCVD or familial amyloidosis. Synthetic mimetics of apoA-I (mutants) may be useful for the treatment of several diseases beyond ASCVD.
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