MOLECULAR SCANNING OF THE INSULIN-RECEPTOR GENE IN SYNDROMES OF INSULIN-RESISTANCE

Using the molecular scanning technique of single-stranded conformation al polymorphism (SSCP), we have examined the exons encoding the insuli n receptor gene in 26 patients with syndromes of insulin resistance. W e found 27 variant sequences, 4 of which were mutations that altered a n amino acid. One patient with the Rabson-Mendenhall syndrome was homo zygous for a mutation in the extracellular or-subunit (Ser to Leu(323) ), One type A insulin-resistant patient was heterozygous for Pro to Le u(178), and another type A insulin-resistant patient was heterozygous for a mutation in the COOH-terminus of the receptor (Arg to Gln(1351)) . The previously reported, and probably functionally insignificant, va riant Val to Met(985) was detected in one patient. No missense or nons ense insulin receptor mutations were found in any patients whose insul in resistance was associated with gross obesity, lipoatrophy, or acrom egaloid features. No missense or nonsense mutations were found in subj ects with polycystic ovary syndrome or Syndrome X. Putting these findi ngs in the context of other work in this field, we conclude that subje cts with leprechaunism or Rabson-Mendenhall syndrome have a high proba bility of having a missense or nonsense insulin receptor mutation. Non obese, nondysmorphic, severely insulin-resistant females with hirsutis m, acanthosis nigricans, and menstrual disturbance (type A phenotype) have an intermediate probability of having this type of insulin recept or mutation. Although insulin receptor mutations have been occasionall y described in other phenotypes of insulin resistance, the frequency o f point mutations in the exons of the insulin receptor gene in patient s with those phenotypes appears to be low.