Genotype-phenotype correlation in inherited severe insulin resistance

Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City 84103, USA.
Human Molecular Genetics (Impact Factor: 6.39). 06/2002; 11(12):1465-75.
Source: PubMed


The insulin receptor is a ligand-activated tyrosine kinase. Mutations in the corresponding gene cause the rare inherited insulin-resistant disorders leprechaunism and Rabson-Mendenhall syndrome. Patients with the most severe syndrome, leprechaunism, have growth restriction, altered glucose homeostasis and early death (usually before 1 year of age). Rabson-Mendenhall syndrome is less severe, with survival up to 5-15 years of age. These disorders are transmitted as autosomal recessive traits. Here we report six new patients and correlate mutations in the insulin receptor gene with survival. Patients with leprechaunism were homozygous or compound heterozygous for mutations in the extracellular domain of the insulin receptor and their cells had markedly impaired insulin binding (<10% of controls). Mutations in their insulin receptor gene inserted premature stop codons (E124X, R372X, G650X, E665X and C682X), resulting in decreased levels of mature mRNA, or affected the extracellular domain of the receptor (R86P, A92V, DeltaN281, I898T and R899W). Three patients with Rabson-Mendenhall syndrome had at least one missense mutation in the intracellular domain of the insulin receptor (P970T, I1116T, R1131W and R1174W). Expression studies in CHO cells indicated that the R86P, A92V, DeltaN281, I898T, R899W and R1131W mutations markedly impaired insulin binding (<5% of control), while the P970T, I1116T and R1174W mutant receptors retained significant insulin-binding activity. These results indicate that mutations in the insulin receptor retaining residual insulin-binding correlate with prolonged survival in our series of patients with extreme insulin resistance.

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Available from: Daniel Giannella-Neto, Feb 24, 2015
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    • "DNA from 11 unrelated individuals (7 controls and 4 patients with Leprechaunism) was used to determine performance characteristics of this INSR full gene sequencing assay. Of these four patients with Leprechaunism, three of them, referred to here as 452, NY1, and 5880, had previously been described [6] [7] [23] Fibroblasts from each of these patients were received and DNA was extracted by MagNA Pure. The fourth patient with Leprechaunism, SLC, was not previously described but fit the clinical criteria. "
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    ABSTRACT: Mutations in the insulin receptor gene cause the inherited insulin resistant syndromes Leprechaunism and Rabson–Mendenhall syndrome. These recessive conditions are characterized by intrauterine and post-natal growth restrictions, dysmorphic features, altered glucose homeostasis, and early demise. The insulin receptor gene (INSR) maps to the short arm of chromosome 19 and is composed of 22 exons. Here we optimize the conditions for sequencing this gene and report novel mutations in patients with severe insulin resistance.
    Molecular Genetics and Metabolism Reports 12/2014; 1(1). DOI:10.1016/j.ymgmr.2013.12.006
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    • "The α subunits mediate insulin binding and β subunits have tyrosine kinase activity (1). Insulin binds to the α subunit of the receptor and stimulates autophosphorylation and kinase activity of the β subunit (2). The human insulin receptor is coded by the gene INSR, and INSR mutations result in insulin resistance (3). "
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    ABSTRACT: Rabson-Mendenhall syndrome (RMS) is a rare syndrome manifested by extreme insulin resistance with hyperinsulinemia, acanthosis nigricans, tooth dysplasia and growth retardation. Our patient was first noted at the age of 8 months due to pigmentations on skin-folded areas. Initial laboratory tests showed normal fasting glucose (69 mg/dL). Fasting insulin level was severely elevated, up to 554.6 µIU/mL, and c-peptide level was increased, up to 13.81 ng/mL. However, hemoglobin A1c was within normal range (4.8%). He is now 11 yr old. His growth development followed the 5-10th percentile and oral hypoglycemic agents are being administered. The last laboratory results showed insulin 364.1 µIU/mL, C-peptide 4.30 ng/mL, and hemoglobin A1c 7.6%. The boy was a compound heterozygote for the c.90C > A and c.712G > A mutations of the insulin receptor gene, INSR, which are nonsense and missense mutations. In summary, we report the first Korean case of RMS, which was confirmed by two novel mutations of the INSR.
    Journal of Korean medical science 05/2012; 27(5):565-8. DOI:10.3346/jkms.2012.27.5.565 · 1.27 Impact Factor
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    • "Impairment of human Ins receptor (INSR; MIM] 147670) function causes extreme insulin-resistance, which is a syndrome characterized by dysmorphic abnormalities, growth deficiency, and hyperinsulinemia, a condition that causes major damage to the skin and ovaries. The severity of the condition is determined by the degree of functional impairment of the receptor [Longo et al., 2002], which in turn depends on the nature of the mutation and whether one or both alleles are affected. Total loss of function of INSR is lethal shortly after birth [Hone et al., 1995; Joshi et al., 1996; Accili et al., 1996], while patients that suffer from a moderate loss of function often reach adulthood. "
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    ABSTRACT: The metazoan receptors for insulin (INSR), insulin-like growth factor 1 (IGF1R), and other insulin-like molecules are transmembrane tyrosine kinases involved in the regulation of cell size, cell proliferation, development, signaling of nutritional and environmental conditions, and aging. Historically, mutations in the human insulin receptor have been studied because such changes often lead to severe insulin resistance. More recently, amino acid sequence alterations in the insulin receptor-like receptors of Drosophila melanogaster and Caenorhabditis elegans, as well as in the mouse insulin receptor have been the focus of attention. These modifications can have profound effects on growth, body size, metabolism, and aging. To integrate the many findings on insulin/IGF1 receptor structure and function across species we have created "Receptors for Insulin and Insulin-like Molecules" (RILM), a curated computer-based resource that displays residue-by-residue information on sequence homology, three-dimensional structure, structure/function annotation, and documented mutations. The resource includes data obtained from sequence and structure analysis tools, primary database resources, and published reports. The information is integrated via a structure-based multiple sequence alignment of diverse members of the family. RILM was designed to provide easy access to multiple data types that could prove useful in the analysis of the effect of mutations on protein structure and ligand binding within this receptor family. RILM is available at
    Human Mutation 07/2007; 28(7):660-8. DOI:10.1002/humu.20491 · 5.14 Impact Factor
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