Insulin-resistant diabetes associated with partial deletion of insulin-receptor gene

Shimada, Fumiyuki; Taira, Masato; Suzuki, Yoshiyuki; Hashimoto, Naotake; Nozaki, Osamu; Makino, Hideichi; Yoshida, Sho; Taira, Masanori; Tatibana, Masamiti; Ebina, Yasuhiko; Tawata, Masato; Onaya, Toshimasa

doi:10.1016/0140-6736(90)92695-e

Cited by 68 publications

(38 citation statements)

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“…The complementary DNA for the insulin receptor was cloned [8,9], and genetic defects in these patients were examined by analysing the insulin receptor gene [10][11][12][13][14][15][16]. The deletion in the ATP binding site of the tyrosine kinase domain of the insulin receptor gene in patients with type A variant syndrome of insulin resistance was found to result in a decrease in kinase activity [13].In the present report, we describe our findings in a patient with type A insulin resistance with acanthosis nigricans in whom the insulin receptor gene was missing the 14th exon coding outside of the cell membrane in the 13-subunit [17]. We investigated this pedigree clinically as well as biochemically and analyses of the binding and kinase activities of the insulin receptor were made with erythrocytes, cultured fibroblasts and Epstein-Barr (EB) virus transformed lymphocytes from the patient and her family.…”

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confidence: 49%

“…In a genomic analysis of the abnormal band from the proband, we found a partial deletion of insulin receptor gene coding for the ~-subunit. Because of this deletion the 14th exon was removed, the result being alteration of the reading frame which caused a stop codon [17]. Furthermore, examination of the insulin receptor-mRNA level in total R N A by Northern blots made no difference between the proband and control subjects (data not shown).…”

Section: Discussionmentioning

confidence: 99%

“…In the present report, we describe our findings in a patient with type A insulin resistance with acanthosis nigricans in whom the insulin receptor gene was missing the 14th exon coding outside of the cell membrane in the 13-subunit [17]. We investigated this pedigree clinically as well as biochemically and analyses of the binding and kinase activities of the insulin receptor were made with erythrocytes, cultured fibroblasts and Epstein-Barr (EB) virus transformed lymphocytes from the patient and her family.…”

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Defects in insulin binding and receptor kinase in cells from a woman with type A insulin resistance and from her family

et al. 1991

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Summary.Defects in insulin receptor function lead to impairment of the insulin response. We treated a patient with the typical phenotype of type A syndrome of insulin resistance whose insulin receptor seemed to lack the transmembrane region and cytoplasmic domain. Hyperinsulinaemia and resistance to exogenous insulin were evident, and insulin binding to cells and uptake of 2-deoxyglucose into fibroblasts were greatly decreased. Molecular weight of the c~-subunit of the insulin receptor was normal, but autophosphorylation and kinase activity were impaired. In the pedigree analysis, defects in insulin binding were also observed in the mother, maternal grandfather and two maternal aunts, corresponding with the abnormality of the insulin receptor gene and mild insulin resistance. In the mother, much the same kinase defects as were seen in the patient became evident. However, no relatives had clinical symptoms similar to those seen in the patient. In the father there was a mild insulin resistance in the glucose clamp study and a borderline impaired glucose tolerance. Although insulin binding to cells was normal in the father, both autophosphorylation and kinase activity were reduced. Our findings suggest that insulin resistance in the patient may be caused by the defects in insulin receptor kinase activity as well as by a reduction in insulin binding activity.Key words: Insulin receptor, type A syndrome of insulin resistance, insulin binding, autophosphorylation, kinase activity.The action of insulin at the cellular level is initiated by insulin binding to its receptor, with which the kinase is activated [1]. These events result in phosphorylation of the ~3-subunit on the tyrosine residues, and in an increase in kinase activity toward exogenous substrates. Therefore, a defect in insulin binding and/or receptor kinase activity is closely linked to impairment of insulin action at the cellular level.Type A syndrome of insulin resistance is characterized by hyperinsulinaemia, resistance to exogenous insulin, acanthosis nigricans, polycystic ovaries and hyperandrogenism [2]. The pathogenesis of these disorders has not been clarified but alterations in the insulin receptor have been noted on both freshly isolated and cultured cells from these patients. This would suggest that a primary defect at the cellular level exists in these patients. In most patients with type A syndrome of insulin resistance, there is a decrease in the kinase activity in proportion to a decrease in receptor number [3][4][5]. In some patients, however, there is a decrease in kinase activity without alteration in insulin binding [4][5][6][7]. The complementary DNA for the insulin receptor was cloned [8,9], and genetic defects in these patients were examined by analysing the insulin receptor gene [10][11][12][13][14][15][16]. The deletion in the ATP binding site of the tyrosine kinase domain of the insulin receptor gene in patients with type A variant syndrome of insulin resistance was found to result in a decrease in kinase activity [13].In the presen...

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Section: Discussionmentioning

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Defects in insulin binding and receptor kinase in cells from a woman with type A insulin resistance and from her family

et al. 1991

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“…Indeed, many mutations of the insulin receptor gene have been identified over the past few years in patients with insulin resistance. 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].…”

Section: Introduction 2 Experimentalmentioning

confidence: 99%

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

1994

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We analysed the biochemical properties of insulin receptors of a Type A insulin resistant patient with a single heterozygous point mutation substituting Gln for Arg 1174. Insulin binding capacity and affinty to Epstein-Barr virus transformed lymphocytes was normal. Quantitative analysis of autophosphorylation and substrate phosphorylation of soluble insulin receptors isolated from patient cells revealed no differences in the basal state whereas in the presence of insulin autophosphorylation activity was only 30% of control receptors. The stimulation of substrate phosphorylation and down-regulation of receptors on patient cells after chronic exposure to insulin was diminished when compared to controls. We conclude that the heterozygous Arg 1174 mutation does not perturb basal kinase activity but specifically interferes with the kinase activation by insulin and that the mutation has a dominant negative effect on the wild type kinase.

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“…Mutations in five genes are known to cause MODY: the glycolytic enzyme glucokinase and the ␤-cell transcription factors; hepatocyte nuclear factor (HNF)-4␣ and -1␣; insulin promoter factor (IPF)-1; and HNF-1␤ (1). Many different types of mutation (including missense, nonsense, frameshift, and splice site mutations) have been described, but there have been no reports of a chromosomal deletion or translocation resulting in MODY, although deletions resulting in inherited syndromes of insulin resistance have been described (3)(4).…”

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Maturity-Onset Diabetes of the Young Caused by a Balanced Translocation Where the 20q12 Break Point Results in Disruption Upstream of the Coding Region of Hepatocyte Nuclear Factor-4α (HNF4A) Gene

et al. 2002

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Monogenic human disorders have been used as paradigms for complex genetic disease and as tools for establishing important insights into mechanisms of gene regulation and transcriptional control. Maturity-onset diabetes of the young (MODY) is a monogenic dominantly inherited form of diabetes that is characterizedM aturity-onset diabetes of the young (MODY) is a monogenic autosomal-dominant subtype of early-onset diabetes due to defective insulin secretion by the pancreatic ␤-cell. Mutations in five genes are known to cause MODY: the glycolytic enzyme glucokinase and the ␤-cell transcription factors; hepatocyte nuclear factor (HNF)-4␣ and -1␣; insulin promoter factor (IPF)-1; and HNF-1␤ (1). Many different types of mutation (including missense, nonsense, frameshift, and splice site mutations) have been described, but there have been no reports of a chromosomal deletion or translocation resulting in MODY, although deletions resulting in inherited syndromes of insulin resistance have been described (3-4).HNF-4␣ (HNF4A) is a member of the nuclear receptor superfamily, and the gene maps to chromosome 20 (20q12) (5). Recently, it has been shown that HNF4A has an alternate distal upstream promoter (P2) that is the major transcription start site in the pancreas (6). This distal promoter is 46 kb 5Ј to the previously identified promoter (P1) of the HNF4A gene and contains binding sites for the transcription factors HNF-1 and IPF-1 (6 -7). A mutation in the IPF-1 binding site of this alternate promoter (P2) cosegregates with diabetes in a large MODY family and adds to the evidence of this transcription factor regulatory network (6 -8).We report a family in which two nonobese female members have young-onset non-insulin-dependent diabetes and recurrent miscarriages. Consistent with a diagnosis of MODY, there are two generations of young-onset non-insulin-dependent diabetes inherited in an autosomaldominant manner with reduced ␤-cell function (clinical details are in RESEARCH DESIGN AND METHODS). Cytogenetic analysis of the proband and her mother showed a female karyotype of 46 chromosomes, with an apparently balanced reciprocal translocation between the short arm of chromosome 3 and the long arm of chromosome 20 [karyotype 46, XX, t(3,20)(p21.2:q12)] (Fig. 1). Karyotype analysis of the proband's second aborted fetus showed an unbalanced translocation. We hypothesized that the break point at 20q12 disrupted the HNF4A gene, resulting in

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Insulin-resistant diabetes associated with partial deletion of insulin-receptor gene

Cited by 68 publications

References 19 publications

Defects in insulin binding and receptor kinase in cells from a woman with type A insulin resistance and from her family

Defects in insulin binding and receptor kinase in cells from a woman with type A insulin resistance and from her family

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

Maturity-Onset Diabetes of the Young Caused by a Balanced Translocation Where the 20q12 Break Point Results in Disruption Upstream of the Coding Region of Hepatocyte Nuclear Factor-4α (HNF4A) Gene

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Insulin-resistant diabetes associated with partial deletion of insulin-receptor gene

Cited by 68 publications

References 19 publications

Defects in insulin binding and receptor kinase in cells from a woman with type A insulin resistance and from her family

Defects in insulin binding and receptor kinase in cells from a woman with type A insulin resistance and from her family

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

Maturity-Onset Diabetes of the Young Caused by a Balanced Translocation Where the 20q12 Break Point Results in Disruption Upstream of the Coding Region of Hepatocyte Nuclear Factor-4α (HNF4A) Gene

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