ALTERNATIVE SPLICING OF THE INSULIN-RECEPTOR ISOFORMS IS ALTERED IN PATIENTS WITH LEPRECHAUNISM

Leprechaunism is a syndrome of severe insulin resistance. In general, mutations in both alleles of the insulin receptor are required for dev eloping the leprechaun phenotype. Recently, we described a leprechaun patient having an Arg for Gly substitution in one allele of the insuli n receptor whereas the other allele has the normal sequence. To explai n the leprechaun phenotype, we searched for additional defects at the receptor level. The insulin receptor exists as two splice variants, ei ther with (B form) or without exon 11 (A form). It has been suggested that a decrease in the relative amount of the A isoform can contribute to the development of an insulin resistant state. Fibroblasts from th e leprechaun patient show levels of the A isoform of less than 20% whe reas in control fibroblasts approximately 50% of the A isoform is pres ent. However, in fibroblasts from two other patients with severe insul in resistance where the disease has been demonstrated to result from t wo mutated insulin receptor alleles, the same decline of the A isoform was seen. We conclude that the decrease in the relative amount of the A isoform in these patients is probably an epiphenomenon due to impai red insulin action.