| Research Abstract |
We investigated the genetic basis of nine families of syndrome of extreme insulin resistance and identified missense mutations of insulin receptor gene in six families, i.e., Arg^<735>->Ser^<735>, pro^<193>->Leu^<193>, Ala^<1048>->Asp^<1048>, Glu^<1179>->Asp^<1179> and Trp^<1193>->Leu^<1193>. The mechanisms of insulin resistance for each mutations were investigated to show as follows. Ala^<1048>->Asp^<1048> in the tyrosine kinase domain of beta subunit caused decreased tyrosine kinase activity. In other five families, decreased insulin binding was responsible for their insulin resistance. Among these mutations, Arg^<735>->Ser^<735> caused decreased insulin binding affinity and others were responsible for decreased receptor number on the cell surface, i.e., mutant insulin receptors with these mutations were not transported to the plasma membrane because of impaired processing of synthesized receptors. We have clarified a novel mechanism of decreased receptor nember in mutations Clu^<1179>->Asp^<1179> and Trp^<1193>->Leu^<1193>. When expressed in COS 7 cells, most of the mutant receptors were degraded in the biosynthetic process and only part of the receptors were able to be transported to the plasma membrane.
In another family with decreased expression of insulin receptor mRNA, we studied promoter region of insulin receptor gene and observed that nucleotide sequence in GC box around position -603 was variable in the patient and control subjects. However, promoter activity was not decreased in the case of the patient. Therefore, unidentified abnormalities in regulatory region which was not studied may responsible for the decrease expression of insulin recepotor gene.
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