A mutation in the insulin receptor gene that impairs transport of the receptor to the plasma membrane and causes insulin-resistant diabetes.

Accili, Domenico; Frapier, C; Mosthaf, Luitgard; McKeon, Catherine; Elbein, Steven C.; Permutt, M. A.; Ramos, Edward; Lander, Eric S.; Ullrich, Axel; Taylor, Simeon I.

doi:10.1002/j.1460-2075.1989.tb08388.x

Cited by 151 publications

(104 citation statements)

References 53 publications

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“…But these different maturation steps proceed at a slower rate in IR R252C than in IRwt. These results are in agreement with previous studies showing that mutations in the N-terminal half of the α-subunit could impair intracellular transport [28,29,30,31,32,33]. One possible interpretation of these events is a misfolding of the protein in the endoplasmic reticulum.…”

Section: Discussionsupporting

confidence: 93%

An arginine to cysteine252 mutation in insulin receptors from a patient with severe insulin resistance inhibits receptor internalisation but preserves signalling events

et al. 2002

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Aims/hypothesis. We examined the properties of a mutant insulin receptor (IR) with an Arg 252 to Cys (IR R252C ) substitution in the α-subunit originally identified in a patient with extreme insulin resistance and acanthosis nigricans. Methods. We studied IR cell biology and signalling pathways in Chinese Hamster Ovary cells overexpressing this IR R252C . Results. Our investigation showed an impairment in insulin binding to IR R252C related mostly to a reduced affinity of the receptor for insulin and to a reduced rate of IR R252C maturation; an inhibition of IR R252C -mediated endocytosis resulting in a decreased insulin degradation and insulin-induced receptor down-regulation; a maintenance of IR R252C on microvilli even in the presence of insulin; a similar autophosphorylation of mutant IR R252C followed by IRS 1/IRS 2 phosphorylation, p85 association with IRS 1 and IRS 2 and Akt phosphorylation similar to those observed in cells expressing wild type IR (IRwt); and finally, a reduced insulin-induced Shc phosphorylation accompanied by decreased ERK1/2 phosphorylation and activity and of thymidine incorporation into DNA in cells expressing IR R252C as compared to cells expressing IRwt. Conclusion/interpretation. These observations suggest that: parameters other than tyrosine kinase activation participate in or control the first steps of IR internalisation or both; IR-mediated IRS 1/2 phosphorylation can be achieved from the cell surface and microvilli in particular; Shc phosphorylation and its subsequent signalling pathway might require IR internalisation; defective IR endocytosis correlates with an enhancement of some biological responses to insulin and attenuation of others. [Diabetologia (2002) 45:657-667]

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Section: Discussionsupporting

confidence: 93%

An arginine to cysteine252 mutation in insulin receptors from a patient with severe insulin resistance inhibits receptor internalisation but preserves signalling events

et al. 2002

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“…NIH-3T3 fibroblasts transfected with expression plasmids encoding the wild-type human insulin receptor (WT) or the Va1382 mutant receptor (Va1382) have been described in previous studies [3,4,9]. Expression vectors for the Val'*'-or Leu"' -mutant insulin receptors were generated 0014-5793/94/$7.00 0 1994 Federation of European Biochemical Societies.…”

Section: Cell Linesmentioning

confidence: 99%

“…codon 382 (TTCphej was reDlaced bv CTCL"" using a mutagenic oligonucleotide 'corresponding ti the same cDNA seque&e indicated above. Mutant cDNAs were then cloned in a SV40-based expression plasmid and transfected in NIH 3T3 cells as described before [3]. The presence of the point mutations at codons 381 and 382 was confirmed using a reverse transcriptase/polymerase chain reaction assay IRT/FCR) to amplify a fragment of human insulin receptor cDNA encompassing nucleotides 1,199-l ,308 [ 121 as described previously [3].…”

Section: Cell Linesmentioning

confidence: 99%

“…For example, substitution of Lys for Asn" is associated with a reduced affinity of the receptor to bind insulin [5], and substitution of Val for Phe3" is associated with reduced insulin-induced phosphorylation of the p-subunit [9,IO]. Substitution of Val for Phe382 was the first mutation reported to interfere with transport of the insulin receptor to the cell surface [3]. In the present study, we have used site-directed mutagenesis to further analyze the effect of replacing amino acids Phe3*l and Phe382 in the primary sequence of the insulin receptor.…”

Section: Introductionmentioning

confidence: 99%

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Mutagenesis of Phe³⁸¹ and Phe³⁸² in the extracellular domain of the insulin receptor: effects on receptor biosynthesis, processing, and ligand‐dependent internalization

et al. 1994

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Mutations of the extracellular domain of the insulin receptor impair processing and transport of receptors to the plasma membrane. We have previously reported that a mutation substituting Val for Phe 382 in the cl-subunit of the insulin receptor impairs intracellular processing and insulin-induced autophosphorylation of the mutant receptor. In this investigation, we have generated two independent mutations of amino acids Phe38' and Phe'*' of the insulin receptor: Val for Phe38' and Leu for Phe'82. These substitutions cause a slight impairment of intracellular processing and transport of the mutant receptors. Furthermore, insulin-dependent internalization of the mutant receptors is unaffected by these mutations. Thus, of the three substitutions studied to date, Val for Phe 382 is the only mutation of the Phe38'-Phe382 sequence that causes a major defect in posttranslational processing of the receptor.

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“…However, partially purified insulin receptors of PK were not autophosphorylated by incubation with IGF-I, indicating that IGF-I cannot activate the insulin receptor kinase in these cells. Several missense mutations have been characterized in the N-terminal c~-subunit of the insulin receptor which are all associated with incomplete processing and defective transport [36,[44][45][46][47][48] to the plasma membrane. Cor- Fig.6.…”

Section: Discussionmentioning

confidence: 99%

An in-frame insertion in exon 3 and a nonsense mutation in exon 2 of the insulin receptor gene associated with severe insulin resistance in a patient with Rabson-Mendenhall syndrome

Müller‐Wieland

Vorm²,

Streicher

et al. 1993

Diabetologia

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Summary.We have studied the structure and function of the insulin receptor in a patient (PK) with severe insulin resistance and Rabson-Mendenhall syndrome. Insulin binding to cultured fibroblasts from PK was almost not detectable and insulin-induced insulin receptor autophosphorytation and glucose uptake was abolished. The structure of the receptor gene was analysed by sequencing amplified products of the 22 exons with the flanking intron regions directly as well as after subcloning in pUCBM20 plasmids. Two mutant alleles of the insulin receptor gene were detected. One allele contains in-frame 12 additional base pairs in exon 3 coding for the amino acids Leu-His-Leu-Val located between Asp-261 and Leu-262 in the receptor's extracellular domain, being the first report of an insertion mutation of the insulin receptor gene. In the other allele Arg-86 in exon 2 is changed into a stop codon. Therefore, PK is compound heterozygous at the insulin receptor locus. Direct cDNA sequencing indicates that both mutant alleles are expressed in the patient's fibroblasts. Studies of the parents' fibroblasts revealed that PK inherited the insertion mutation from the father and the nonsense mutation from the mother. Insulin binding to fibroblasts of the mother was reduced (63 % of control cells) and hormone binding to the father's cells shows a larger reduction (37 % of control cells), but less severe than the patient's cells (11% of control). This investigation provides further evidence that the Rabson-Mendenhall syndrome is causally related to mutations in the insulin receptor gene.

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A mutation in the insulin receptor gene that impairs transport of the receptor to the plasma membrane and causes insulin-resistant diabetes.

Cited by 151 publications

References 53 publications

An arginine to cysteine252 mutation in insulin receptors from a patient with severe insulin resistance inhibits receptor internalisation but preserves signalling events

An arginine to cysteine252 mutation in insulin receptors from a patient with severe insulin resistance inhibits receptor internalisation but preserves signalling events

Mutagenesis of Phe³⁸¹ and Phe³⁸² in the extracellular domain of the insulin receptor: effects on receptor biosynthesis, processing, and ligand‐dependent internalization

An in-frame insertion in exon 3 and a nonsense mutation in exon 2 of the insulin receptor gene associated with severe insulin resistance in a patient with Rabson-Mendenhall syndrome

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A mutation in the insulin receptor gene that impairs transport of the receptor to the plasma membrane and causes insulin-resistant diabetes.

Cited by 151 publications

References 53 publications

An arginine to cysteine252 mutation in insulin receptors from a patient with severe insulin resistance inhibits receptor internalisation but preserves signalling events

An arginine to cysteine252 mutation in insulin receptors from a patient with severe insulin resistance inhibits receptor internalisation but preserves signalling events

Mutagenesis of Phe381 and Phe382 in the extracellular domain of the insulin receptor: effects on receptor biosynthesis, processing, and ligand‐dependent internalization

An in-frame insertion in exon 3 and a nonsense mutation in exon 2 of the insulin receptor gene associated with severe insulin resistance in a patient with Rabson-Mendenhall syndrome

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Mutagenesis of Phe³⁸¹ and Phe³⁸² in the extracellular domain of the insulin receptor: effects on receptor biosynthesis, processing, and ligand‐dependent internalization