A leucine-to-proline mutation in the insulin receptor in a family with insulin resistance.

Abstract

We have determined the primary structure of a mutant insulin receptor of a leprechaun patient born from a consanguineous marriage. A characteristic feature of leprechaunism is an extreme resistance to insulin. In this patient the insulin resistance seems to result from an observed lack of insulin binding to intact cells. Solubilizanion of cells in non-ionic detergents leads to the appearance of insulin receptors which can bind insulin. However, the insulin-stimulated autophosphorylation of the receptor's : subunit is markedly reduced. Cloning and sequencing of cDNA derived from insulin receptor mRNA of this patient revealed a leucine-to-proline mutation at position 233 in the a subunit. By means of DNA amplification we found that the patient is homozygous for this mutation and that the parents and two grandparents from the consanguineous line are heterozygous. The heterozygous individuals all show decreased insulin binding to cultured fibroblasts. In addition, they are mildly insulin resistant in vivo. These observations show a linkage between the leucine-to-proline mutation and the observed insulin resistance in this family. We therefore conclude that the mutation in the homozygous form is responsible for the extreme insulin resistance in the leprechaun patient. The mutation for the first time characterizes a region in the insulin receptor which seems to be involved in transmitting the insulin binding signal to the tyrosine kinase domain.

Five mutant alleles of the insulin receptor gene in patients with genetic forms of insulin resistance.

“…This study supports the growing body of evidence that mutations in the insulin receptor gene are the cause of genetic syndromes associated with extreme insulin resistance such as leprechaunism, type A extreme insulin resistance, and the Rabson-Mendenhall syndrome (1)(2)(3)(4)(5)(6)(7)(8)(19)(20)(21). The application of the polymerase chain reaction combined with direct sequencing of amplified genomic DNA greatly facilitates determinations of nucleotide sequence and identification of mutations (3,22,23).…”

Altered expression of insulin receptor types A and B in the skeletal muscle of non-insulin-dependent diabetes mellitus patients.

“…Abnormal insulin receptor function has been reported in rare syndromes of extreme insulin resistance (19)(20)(21)(22)(23)(24)(25)(26)(27) as well as in NIDDM (28)(29)(30)(31). Although in some recently reported cases receptor dysfunction in syndromes of extreme insulin resistance could be attributed to mutations in the insulin receptor gene (19,20,24,32), the cause of the altered receptor kinase activity in NIDDM is thus far unclear.…”

Individuals with only one allele for a functional insulin receptor have a tendency to hyperinsulinaemia but not to hyperglycaemia

“…The parents of the patient (329 and 330) and the grandparents from the consanguineous line (327 and 328) were found to be heterozygous for the mutation. The grandfather (326) who maps outside the consanguineous line and 21 control individuals did not have this mutation [3]. The levels of a25I-insutin binding to fibroblasts from the members of this family are given in Figure 2.…”

“…This leprechaun patient is homozygous for a genetic defect in the insulin receptor which was recently found to be a leucine to proline mutation at position 233 in the receptor a-chain [3]. This defect is expressed as an almost complete absence of insulin binding to cultured fibroblasts and a severe decrease of insulin stimulated autophosphorylation of the [~-subunit of the insulin receptor [4].…”