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: 6.68). 06/2002; 11(12):1465-75.
Source: PubMed

ABSTRACT 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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    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.
    01/2014; 1. DOI:10.1016/j.ymgmr.2013.12.006
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    ABSTRACT: The effects of co-administration of aqueous extract of whole plant of Cassia auriculata and pioglitazone were investigated in alloxan treated diabetic rats. Alloxan monohydrate (150mg/kg, i.p.) was administered to 24 hrs fasted rats to induce diabetes. Animals with blood glucose levels of 200-350 mg/dl after 48 hrs of alloxan administration were considered as diabetic. Different groups of diabetic animals were then treated with pioglitazone alone (10 mg/kg, p.o.; 100%), C.auriculata alone (450 mg/kg, p.o.; 100%); and 50%:50% and 25%:75% combinations of both pioglitazone and C.auriculata, respectively for a period of 28 days. On the 0 th , 7 th , 14 th , 21 st and 28 th day of treatment, blood was collected and the serum levels of glucose and antioxidant parameters like TBARS, catalase and GSH were estimated. The study revealed a prominent positive effect of 25%:75% combination of pioglitazone and Cassia auriculata suggesting that a reduction of 75% of the conventional dose of pioglitazone (ie. administering only 25% dose of pioglitazone) supplemented/combined with 75% dose of C. auriculata (25% reduction in dose), produced anti-diabetic effects comparable to that of 100% pioglitazone (10 mg/kg) with comparatively more protective effect against free radical induced oxidative stress. This study thus suggests the beneficial use of combination of pioglitazone and C. auriculata over administration of pioglitazone alone for the effective treatment of diabetes and its associated oxidative stress. Clinical feasibility of the beneficial effect of this combination in diabetic patients needs to be confirmed. INTRODUCTION Diabetes mellitus is one of the most common and widely occurring chronic diseases all over the world. The prevalence of diabetes has reached epidemic proportions. About 1.3% of the population suffers from this disease throughout the world. In 2010, 285 million people, corresponding to 6.4% of the world's adult population, suffered with diabetes. The number is expected to grow to 438 million by 2030, corresponding to 7.8% of the adult population. India is the diabetic capital of the world and 7 out of every 100 adult are diabetic. It affects up to 10% of the population aged 20 years and older. This rate may be doubled if those with impaired glucose tolerance (IGT) are also included 1 .
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    ABSTRACT: Rabson-Mendenhall syndrome (RMS) is a rare genetic disorder characterized by growth retardation, dysmorphisms, lack of subcutaneous fat, acanthosis nigricans, enlarged genitalia, hirsutism, dysplastic dentition, coarse facial features, abnormal glucose homeostasis, hyperinsulinemia and pineal hyperplasia. Herein, we describe a 13-year-old girl with physical features of RMS who presented to us on account of acanthosis nigricans.
    Indian Journal of Dermatology 01/2014; 59(6):633. DOI:10.4103/0019-5154.143579

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