Introduction

As has been amply documented by preceding chapters, the structures of hormone genes, related mRNAs and precursor polypeptides are critical to determining the nature of peptides secreted from the pancreatic islet. Whereas transcription of the human insulin gene can be expected usually to result in the formation of normal insulin in normal amounts, five classes of insulin gene mutations might affect the complex processes of insulin biogenesis. As illustrated by Fig. 13.1, mutations might alter (a) the rate of control of insulin gene transcription (by affecting promoter, enhancer, termination or other elements); (b) the efficiency or correctness of processing of the corresponding mRNA precursor (by interfering with excision of intervening sequences, 5′- capping or 3'-polyadenylation); (c) the rate or control of translation of mature mRNA (by altering ribosome binding sites, regulatory regions or mRNA stability); (d) the length of the product of insulin mRNA translation (by changing the position of the first stop codon encountered during the process); or (e) the amino acid sequences of peptides resulting from the accurate and controlled translation of insulin mRNA. The last group of mutations could involve (a) amino acid replacements in the signal peptide region in preproinsulin (leading to failure of the precursor to be translocated from the cytoplasm to the cisternum of the rough endoplasmic reticulum, or to failure of the precursor to be sorted to the Golgi apparatus and secretion granules); (b) replacements at critical processing sites in proinsulin (leading to failure of the hormone precursor to be converted enzymatically to insulin); or (c) replacements in the regions of the insulin A- and B-chains (leading ultimately to the formation of products with altered structures).