An unusual phenotype of hereditary AApoAI amyloidosis caused by a novel Asp20Tyr substitution is linked to pH-dependent aggregation of apolipoprotein A-I.

Apolipoprotein A-I (apoA-I) plays beneficial roles as the major structural and functional protein on plasma high-density lipoproteins (HDL). However, APOA1 gene mutations can cause protein misfolding and pathologic amyloid deposition in various organs in human hereditary AApoAI amyloidosis, a potentially lethal systemic disease. We report esophageal and duodenal AApoAI amyloidosis in a 56-year-old patient with Barrett's esophagus, a condition involving chronic acid reflux. Amyloid deposits contained full-length apoA-I featuring a novel D20Y mutation identified by gene sequencing and protein mass spectrometry. Genetic analysis of asymptomatic family members revealed autosomal dominant inheritance. Fibril formation by the full-length variant apoA-I rather than its fragments and the location of the mutation in a conserved amyloid-prone N-terminal segment were highly unusual for hereditary AApoA-I amyloidosis. Structural and stability studies of the recombinant D20Y and wild-type apoA-I showed small but significant mutation-induced structural perturbations in the native lipid-free protein at pH 7.4. Major destabilization and aggregation of the variant protein were observed at pH 4.0. We propose that acidic conditions in Barrett's esophagus promoted protein misfolding and amyloid formation by the D20Y variant. These findings expand our understanding of the clinical features and molecular basis of AApoAI amyloidosis and suggest clinical strategies.