Mutant DNA encoding insulin receptor substrate 1

Details Mutant DNA encoding insulin receptor substrate 1 Mutant DNA encoding insulin receptor substrate 1

1996-02-12

1998-10-27

Chambers, Jasemine C.

Chemistry: molecular biology and microbiology

Vector, per se

435325, 4351723, 800 2, 530350, 536 231, 536 235, C12N 1500, C12N 500, C07K 100, C07H 2104

Patent

active

058277307

DESCRIPTION:

BRIEF SUMMARY
CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of PCT/DK94/00227 filed Jun. 10, 1994, which is incorporated herein by reference.


FIELD OF INVENTION

The present invention relates to a mutant DNA sequence encoding insulin receptor substrate 1, a method of detecting a mutation in the gene encoding insulin receptor substrate 1, as well as a diagnostic composition and a test kit for use in the method.


BACKGROUND OF THE INVENTION

Non-insulin-dependent diabetes mellitus (NIDDM) is a common endocrine disorder and a considerable body of evidence strongly suggests that genetic factors contribute to the pathogenesis (1). Studies of patients with overt NIDDM and of individuals at high risk of NIDDM reveal abnormalities of both insulin secretion and insulin action (2). However, a genetic defect at one or more loci in the cellular action of insulin and insulin-like growth factor 1 (IGF1) might well involve both the biochemical pathways of tissues that regulate insulin secretion and insulin sensitive hepatic and extrahepatic tissues that produce or extract glucose.
Although more than twenty different mutations of the insulin receptor gene have been reported in syndromes of severe insulin resistance frequently associated with the skin disorder acanthosis nigricans or ovarian hyperandrogenism (17), mutations in the insulin receptor molecule do not explain the genetic etiology of the common form of NIDDM.
The common form of late onset NIDDM is a heterogeneous disorder where at least two major defects contribute to the pathophysiology of the phenotype: insulin resistance and insulin deficiency (2). Most likely NIDDM is also polygenic and it is suggested that subsets of patients will display changes in various genes, in aggregate accounting for the inherited components of the disorder. The high cumulative risk of diabetes in offspring of NIDDM parents (30-50%) and the high concordance rate in identical twins (70-100%) underscore the significance of the genetic etiology of the disease (1).
Insulin initiates its cellular effects by binding to the a subunit of its tetrameric plasma membrane receptor (3). The kinase in the .beta. subunit is thereby activated which in turn catalyzes the intramolecular autophosphorylation of specific tyrosine residues of the .beta. subunit, further stimulating the tyrosine kinase activity of the receptor towards other protein substrates in the cascade of insulin action.
Recently, the first endogeneous substrate for the insulin receptor kinase (termed insulin receptor substrate 1, abbreviated to IRS-1) was cloned and sequenced (4-6). The complementary DNA sequence encodes a cytoplasmic, hydrophilic protein of a relative molecular mass between 165 and 185 kD (27,28) which contains multiple phosphorylation sites. Besides being a substrate for the insulin receptor kinase, IRS-1 is also phosphorylated following the activation of the IGF1 receptor kinase (16).
IRS-1 is barely detectable in cells expressing few insulin receptors, but is strongly detected in cells expressing high levels of receptors and weakly detected in cells expressing mutant receptors defective in biological signalling (27,28). IRS-1 is a unique molecule containing 20 tyrosine phosphorylation consensus sequences, 6 of which appear in YMXM (Tyr-Met-X-Met) motifs. Following insulin stimulated tyrosine phosphorylation of YMXM motifs in the IRS-1 molecule, the phosphorylated IRS-1 binds phosphatidylinositol 3-kinase (PI3-kinase) suggesting that IRS-1 acts as a multisite "docking" protein to bind signal proteins thereby linking the receptor kinase to insulin sensitive transporters and enzymes (7-15). The PI3-kinase is composed of at least two subunits including a 110 kDa catalytic subunit and a 85 kDa regulatory protein which contains src homology 2 domains that mediate protein-protein interactions by binding to phosphotyrosine residues in various proteins (7-15). Interestingly, it has been demonstrated that insulin causes the interaction between IRS-1 and PI-3 kinase via phosphorylated YMXM motifs of IRS-

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