Title : Substitution of arginine for histidine at position 209 in the alpha- subunit of the human insulin receptor
Abstract :
A mutation that impairs receptor dimerization and transport of receptors to the cell surface
Receptors for insulin and epidermal growth factor contain cysteine-rich domains in the extracellular portion of the molecule
His209 ( insulin receptor numbering system) is 1 of 2 amino acid residues that are identically conserved in the cysteine-rich domains of insulin receptors , epidermal growth factor receptors , and other homologous receptors
Previously, we have identified a patient with leprechaunism who is homozygous for a mutation substituting Arg for His209 in the insulin receptor gene (Kadowaki, T., Kadowaki, H., Rechler, M. M., Serrano-Rios, M., Roth, J., Gorden, P., and Taylor, S. I. (1990) J. Clin
Invest
86, 254-264)
In this investigation, the Arg209 mutant receptor was expressed by transfection of mutant cDNA into NIH-3T3 cells
The mutation impairs several steps in the post-translational processing of the insulin receptor : dimerization of 190-kDa proreceptors into a disulfide linked species, proteolytic cleavage of the pro receptor into alpha- and beta- subunits , and terminal processing of the high mannose form of N-linked oligosaccharide into complex carbohydrate
In addition, the defects in post-translational processing within the endoplasmic reticulum and Golgi apparatus are associated with a marked inhibition in transport of receptors to the plasma membrane
Nevertheless, a small number (approximately 10%) of the receptors are transported to the cell surface
These receptors on the cell surface bind insulin with normal affinity and have normal tyrosine kinase activity