Hepatic amyloidosis resulting from deposition of the apolipoprotein A-I variant Leu75Pro

Abstract

Apolipoprotein A-I amyloidosis (AApo A-I) is an inherited Jystemic disease that results fiom pathologic deposition in tissues of fibrils composed of Apo A-I-related molecules. This disorder has been linked to mutations occurring within the coding region of the Apo A-I gene and heretofore, nine such variants had been described. Recently, a tenth alteration was found in an Italian population where the substitution of proline for leucine at position 75 (Leu75Pro) was associated with amyloid deposits in the liver. We now report our studies on a patient of different ethnicity who has hepatic amyloidosis and a similar mutation in the amyloidogenic precursor protein, as evidenced fiom analyses ofgenomic Apo A-I-encoding DNA. Additionally, fibrils extractedfiom the liver and characterized chemically were found to be composed almost exclusively of a ~ 96 residue N-terminal Apo A-1 fiagment that contained the Leu75 Pro substitution. RFLP analyses revealed that the patient was heterozygous for this mutation; however, <10% of the plasma Apo A-I consisted of the aberrant protein while the remainder had the normal (wild-Type) sequence. Our findings provide further evidence that the Leu75Pro variant is associated with a predominant hepatic phenotype and can occur in individuals of diverse ethnic backgrounds.

Key Words:

• amyloidosis
• hepatic amyloid
• Apolipoprotein A-I
• variant gene
• mass spectrometry