Islet amyloid polypeptide (IAPP): structure of its cDNA and gene and the identification of species differences of importance for islet amyloid formation.

Abstract

The human islet amyloid polypeptide (IAPP) cDNA and gene have been characterized. The cDNA sequence predicts an 89-amino-acid precursor protein from which the ST-amino-acid mature IAPP peptide is formed by N-and C-terminal proteolytic processing. The presence of conserved proteolytic cleavage sites indicate that the IAPP molecule is a normal secretory product of the pancreatic β-cell. Sequence analysis of the normal IAPP gene also indicates that IAPP found in islet amyloid is not mutated. The IAPP gene consists of at least 3 exons of which the first exon is non-coding, the second exon encodes the signal peptide and part of the N-terminal prosequence and the third exon encodes the remainder of that sequence, the IAPP peptide and the C-terminal prosequence. IAPP mRNA was found exclusively in β-cells of the islets of Langerhans. A functional and tissue-specific promoter region was identified in the 5’ flanking sequence of the gene. The human IAPP gene mapped to two regions of chomosome 12. Finally, analysis of the IAPP cDNA sequence in several species with or without tendency to develop islet amyloid demonstrated differences in a part of the IAPP molecule which is likely to determine its amyloidogenic properties.