We studied the structure of the
insulin-receptor gene in normal individuals and in four unrelated patients with
leprechaunism (Minn-1, Ark-1, Ark-2, Can-1) and four unrelated patients with the type A syndrome of
insulin resistance, both disorders associated with genetic alterations in affinity, binding capacity, and
kinase activity of the
insulin receptor. Genomic cloning and Southern blot analysis indicate that the normal human
insulin-receptor gene is greater than or equal to 150 kilobases long and consists of a minimum of 17 exons, 6 in the genomic region of the alpha-subunit and 11 in the region of the beta-subunit. Three of the patients, one with
leprechaunism and two with type A syndrome, have decreases in
insulin-receptor mRNA but on genomic blot analysis have no obvious abnormalities in the
insulin-receptor gene. No distinctive pattern of restriction-fragment-length polymorphisms or evidence for major insertion or deletion mutations of the
insulin-receptor gene was found in any of the patients. These data indicate that the
insulin-receptor gene is greater than 35 times larger than coding regions and has a complex structure. Although
leprechaunism and type A syndrome are most likely due to defects in the structure and expression of the
insulin-receptor gene, they are likely to be associated with specific point mutations rather than major changes in gene structure.