Tangier disease. The complete mRNA sequence encoding for preproapo-A-I

Abstract

A cDNA library of Tangier liver mRNA has been established, and two apo-A-I-containing clones were identified. The complete derived amino acid sequence of preproapo-A-I has been established by nucleic acid sequence analysis of cloned apo-A-I cDNA and specific primer extensions on Tangier liver RNA. Sequence analysis of the longest cDNA clone, pMDB136T, established the derived amino acid sequence of residues 116-243 of plasma apo-A-I. The remaining portion of the sequence of Tangier preproapo-A-I mRNA was established by sequence analysis of specific primer extensions of synthetic oligonucleotides on Tangier liver mRNA. This latter technique provided the derived amino acid sequence of residues -24 to 116, thus completing the entire preproapo-A-I structure. The structure of Tangier preproapo-A-I was identical to normal preproapo-A-I except for a single base substitution (G----T) which resulted in the isosteric replacement of a glutamic acid residue at position 120 to aspartic acid. These results are interpreted as indicating that there is no major structural defect in Tangier apo-A-I, and the rapid rate of catabolism of apo-A-I in Tangier disease is due to a post-translational defect in apo-A-I metabolism.