Human Diabetes Associated with a Deletion of the Tyrosine Kinase Domain of the Insulin Receptor

Abstract

The insulin receptor has an intrinsic tyrosine kinase activity that is essential for signal transduction. A mutant insulin receptor gene lacking almost the entire kinase domain has been identified in an individual with type A insulin resistance and acanthosis nigricans. Insulin binding to the erythrocytes or cultured fibroblasts from this individual was normal. However receptor autophosphorylation and tyrosine kinase activity toward an exogenous substrate were reduced in partially purified insulin receptors from the proband's lymphocytes that had been transformed by Epstein-Barr virus. The insulin resistance associated with this mutated gene was inherited by the proband from her mother as an apparently autosomal dominant trait. Thus a deletion in one allele of the insulin receptor gene may be at least partly responsible for some instances of insulin-resistant diabetes.

Functional properties of a heterozygous mutation (Arg1174 → Gln) in the tyrosine kinase domain of the insulin receptor from a Type A insulin resistant patient

“…In all experiments the autophosphorylation capacity of patient receptors was well below 50% of controls and therefore, the mt kinase negatively affects the wt kinase, most likely within the hybrid receptor structure (mt/wt). This interpretation is consistent with the observation that most of those kinase mutations are inherited as a dominant trait [9,10,31,32,38]. Furthermore, the in vitro assembly of kinase defective receptor halves with wt receptor halves also results in a dominant inhibition of the kinase activity [41,42].…”

“…CHO, NIH-3T3 and COS 7) transfected with the mutated insulin receptor [28][29][30][35][36][37][38] and (ii) Epstein-Barr virus transformed patient lymphocytes [9,11,31,32,39]. The two systems differ profoundly in that the mutated receptor gene in transfected cells is present in a 'homozygous' state so that only mutated receptors are synthesised.…”

“…Inherited defects of the insulin receptor gene may cause diminished receptor expression [1][2][3][4][5][6] or impaired receptor function, i.e. insulin binding [7,8] or tyrosine kinase activity [9][10][11].…”

W mutant mice with mild or severe developmental defects contain distinct point mutations in the kinase domain of the c-kit receptor.

“…Truncated forms of EGFR have been shown to act in a dominantnegative manner in in vitro cell lines [Basu et al 1989). Deletion of the kinase domain of the insulin receptor results in autosomal dominant inheritance of insulin resistance in humans (Kadowaki et al 1988;Taira et al 1989), and a point mutation in the ligand-binding domain of the human insulin receptor confers decreased insulin binding in cell culture and insulin resistance in heterozygote individuals {Klinkhamer et al 1989}.…”

Phenotypical variety of insulin resistance in a family with a novel mutation of the insulin receptor gene

“…Some dozens of mutations in the human insulin receptor gene have already been identified to date [8][9][10][11]. Homozygous or compound-heterozygous mutations in the insulin receptor gene are found in patients with syndromes of severe insulin resistance [12].…”