Deletion of Asn{sup 281} in the {alpha}-subunit of the human insulin receptor causes constitutive activation of the receptor and insulin desensitization

Journal Article · Thu Feb 01 04:00:00 EST 1996 · Journal of Clinical Endocrinology and Metabolism

DOI:https://doi.org/10.1210/jc.81.2.719· OSTI ID:494172

Desbois-Mouthon, C; Sert-Langeron, C; Magre, J; Blivet, M J ^[1]

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1. INSERM, Paris (France); and others

We studied the structure and function of the insulin receptor (IR) in two sisters with leprechaunism. The patients had inherited alterations in the IR gene and were compound heterozygotes. Their paternal IR allele carried a major deletion, including exons 10-13, which shifted the reading frame and introduced a premature chain termination codon in the IR sequence. This allele was expressed at a very low level in cultured fibroblasts (<10% of total IR messenger ribonucleic acid content) and encoded a truncated protein lacking transmembrane and tyrosine kinase domains. The maternal IR allele was deleted of 3 bp in exon 3, causing the loss of Asn{sup 281} in the {alpha}-subunit. This allele generated levels of IR messenger ribonucleic acid and cell surface receptors similar to those seen in control fibroblasts. However, IRs from patients` cells had impaired insulin binding and exhibited in vivo and in vitro constitutive activation of autophosphorylation and tyrosine kinase activity. As a result of this IR-preactivated state, the cells were desensitized to insulin stimulation of glycogen and DNA syntheses. These findings strongly suggest that Asn{sup 281} of the IR {alpha}-subunit plays a critical role in the inhibitory constraint exerted by the extracellular {alpha}-subunit over the intracellular kinase activity. 59 refs., 6 figs.

• OSTI ID: 494172
• Journal Information: Journal of Clinical Endocrinology and Metabolism, Journal Name: Journal of Clinical Endocrinology and Metabolism Journal Issue: 2 Vol. 81; ISSN JCEMAZ; ISSN 0021-972X
• Country of Publication: United States
• Language: English

Related Subjects

55 BIOLOGY AND MEDICINE
BASIC STUDIES
AMINO ACIDS
DNA SEQUENCING
ELECTROPHORESIS
ENZYME ACTIVITY
EXONS
GENE MUTATIONS
GENE REGULATION
GENETICS
GLUCOSE
GROWTH
HEREDITARY DISEASES
HOMEOSTASIS
INSULIN
PATIENTS
PHOSPHORYLATION
PHOSPHOTRANSFERASES
POLYMERASE CHAIN REACTION
RECEPTORS
RECESSIVE MUTATIONS
STRUCTURE-ACTIVITY RELATIONSHIPS
TYROSINE