Restriction fragment length polymorphisms of the insulin receptor gene in families with insulin resistance and leprechaunism.

Restriction fragment length polymorphisms (RFLPs) for the insulin receptor gene were compared among controls and families Atl and Ark-1, whose probands have extreme insulin resistance and leprechaunism. Previous studies indicated that fibroblasts cultured from patients Atl and Ark-1 had less than 10% of normal insulin binding. Cells cultured from the related parents of Atl had partial reduction in insulin binding, suggesting that patient Atl inherited the same mutant allele for the insulin receptor from both his parents. By contrast, the parents of Ark-1 were unrelated and their cells had different degrees of impaired insulin binding, suggesting that patient Ark-1 inherited two different, non-complementing alleles for the insulin receptor. To test these hypotheses, RFLPs were defined for the insulin receptor gene and their transmission was studied in families Atl and Ark-1. Patients affected with leprechaunism had no private polymorphisms in the insulin receptor gene, indicating that gross rearrangements were not present. A polymorphism generated with EcoRI at the 5' end of the insulin receptor gene gave fragments of 16 and 20 kb and was the only one informative in family Atl. Both parents were heterozygous, presenting a 16 and a 20 kb fragment, and transmitted the 20 kb allele to their affected offspring. Ark-1's parents were heterozygous for three different RFLPs, including this EcoRI polymorphism, and patient Ark-1 inherited a different allele for the insulin receptor from each parent. These results support the genetic hypotheses suggested by insulin-binding studies and indicate that RFLPs can be used to identify transmission of the insulin receptor gene in families with insulin resistance.