A mutation (Trp1193?Leu1193) in the tyrosine kinase domain of the insulin receptor associated with type A syndrome of insulin resistance

Abstract

We evaluated a 35-year-old diabetic male patient with type A insulin resistance, showing acanthosis nigricans. Insulin binding to the patient's Epstein-Barr-virus transformed lymphocytes was mildly reduced. The maximal insulin-stimulated autophosphorylation of the insulin receptor from the patient's transformed lymphocytes was decreased to 45% of that from the control subjects. On examination, the biological activities of insulin and insulin-like growth factor I in the patient's cultured fibroblasts, insulin sensitivity of amino isobutyric acid uptake and thymidine incorporation was decreased, but insulin-like growth factor I action was normal. The sequence analysis of amplified genomic DNA revealed that the patient was heterozygous for a mutation substituting Leu for Trp at codon 1193 in exon 20 of the insulin receptor gene. The patient's mother and sister were also heterozygous for a mutation in the insulin receptor gene that substituted Leu for Trp1193 in the beta subunit of the receptor. Therefore, the mutation causes insulin resistance in a dominant fashion. They were less hyperglycaemic and more hyperinsulinaemic than the proband after glucose loading. The mother had diabetes mellitus but did not show acanthosis nigricans, while the sister did not have diabetes and showed acanthosis nigricans. These results suggest that this mutation causes defective tyrosine kinase activity of the insulin receptor, which results in insulin resistance. Insulin action and phenotypic appearance may be mediated by different factors.

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].…”

“…Several other mutations in the regulatory domain of the insulin receptor tyrosine kinase have been reported to alter tyrosine kinase activity: Ala 1134 ---) Thr [28], Ala lm --. Glu [29], Met 1153 ~ Ile [30], Arg 1164 -~ Gln [31], Trp 1193 --) Leu [32] and Trp 12°° -~ Ser [33,34].…”

“…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.…”

Functional Interaction of Caveolin-1 with Bruton's Tyrosine Kinase and Bmx

“…This finding, however, is not without precedence. In fact, point mutations involving the same aromatic residues have also been found in the caveolin-binding domain of the insulin receptor in patients suffering from severe insulin resistance (49,50).…”

Caveolin-1-deficient mice show insulin resistance and defective insulin receptor protein expression in adipose tissue

“…A subset of patients with severe insulin resistance has mutations within the caveolin-binding motif of the insulin receptor (W1193L and W1200S) (9,10,12,17,18,35). These caveolin-binding motif mutations lead to enhanced degradation of the insulin receptor (12,35) (Table 1). Thus a better understanding of the interaction between caveolin-1 and the insulin receptor may lead to the development of new therapies that functionally stabilize insulin receptor protein expression.…”