We studied the
biological properties of
insulin receptors (IRs) and
insulin-like growth factor-I (
IGF-I) receptors in cultured fibroblasts from a patient with
leprechaunism (leprechaun Par-1). Patient cells displayed normal
insulin binding capacity and affinity. Basal in vivo autophosphorylation and in vitro exogenous
kinase activity of patient IRs were elevated twofold to threefold compared with control receptors, and
insulin had no further effect on these processes. Moreover, patient IRs were unable to promote the stimulation of metabolic and mitogenic pathways. IR substrate-1 (IRS-1) and
mitogen-activated
protein (MAP)
kinase tyrosine phosphorylation and
glycogen and
DNA synthesis were not increased in the basal state in patient fibroblasts and were also insensitive to the stimulatory effect of
insulin. As for
IGF-I, although binding and receptor
kinase activity were normal, the ability to stimulate
glycogen and
DNA synthesis was altered in patient cells. Two mutant alleles of the IR gene were detected by denaturing gradient gel electrophoresis (DGGE) and direct sequencing. The maternal allele contained a point mutation in exon 18 encoding the
tryptophan-for-
arginine substitution at position 1092, and the paternal allele had a point mutation in exon 20 substituting
lysine for
glutamic acid at
codon 1179. Thereby, leprechaun Par-1 was a compound heterozygote for two missense mutations located in the IR beta-subunit. The present investigation provides the first evidence that
leprechaunism can be causally related to structural alterations in the
tyrosine kinase domain of the IR. These alterations result in severe impairment of
insulin and
IGF-I action.