THE insulin receptor is a cell surface glycoprotein that mediates the action of insulin upon target cells. The receptor was originally identified by its ability to bind the hormone (1–3). Over the past two decades, considerable progress has been made in defining the structure of the receptor molecule (4–7) as well as the biochemical mechanism by which it mediates insulin action (8–10). In addition, the insulin receptor has been identified as a target for pathological processes in human disease. In this review, we describe mutations in the insulin receptor gene that have been identified in patients with genetic forms of insulin resistance (6). Identification of these mutations has elucidated the molecular mechanisms that cause disease in these patients. In addition, the mutations have provided significant insights into the structure and function of the insulin receptor.

The human insulin receptor gene contains 22 exons, and occupies in excess of 150 kilobase pairs of DNA on the short arm of chromosome 19 (bands pl3.2→pl3.3) (11, 12). Typical of a “housekeeping” type of promoter, the promoter is GC-rich, lacks a TATA box, but contains several Spl binding sites (11, 13–16). In addition, an enhancer element has been identified 410–481 base pairs (bp) upstream from the initiator AUG codon (16). Several potential CAAT/enhancer binding protein (C/EBP) binding sites have been identified in the human insulin receptor gene, two in the 5'-flanking domain and one in the first intron (17). The precise importance of these various potential regulatory sites has not been completely elucidated. In addition, it seems likely there are other regulatory sites in the gene that remain to be identified.