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      Two novel mutations identified in familial cases with Donohue syndrome

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          Abstract

          Donohue syndrome (DS) is a rare and lethal autosomal recessive disease caused by mutations in the insulin receptor ( INSR) gene, manifesting marked insulin resistance, severe growth retardation, hypertrichosis, and characteristic dysmorphic features. We report the clinical, molecular, and biochemical characterization of three new patients with DS, and address genotype–phenotype issues playing a role in the pathophysiology of DS. A female infant born to first-degree cousins Muslim Arab parents and two brothers born to first-degree cousins Druze parents presented classical features of DS with hypertrophic cardiomyopathy and died in infancy. Each patient was found homozygous for one missense mutation within the extracellular domain of the INSR gene. Western blot analysis identified the proreceptor of INSR, but not its mature subunits alpha and beta. Of 95 healthy Muslims, no heterozygous was found and of 52 healthy Druze from the same village, one was heterozygous. This study presents two novel familial mutations in the alpha subunit of the INSR which appear to impair post-translational processing of the INSR, resulting loss of its function. Both mutations cause DS with hypertrophic cardiomyopathy and early death. Identification of the causative mutation enables prevention of this devastating disease.

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          Diabetes and cardiovascular disease. The Framingham study.

          Based on 20 years of surveillance of the Framingham cohort relating subsequent cardiovascular events to prior evidence of diabetes, a twofold to threefold increased risk of clinical atherosclerotic disease was reported. The relative impact was greatest for intermittent claudication (IC) and congestive heart failure (CHF) and least for coronary heart disease (CHD), which was, nevertheless, on an absolute scale the chief sequela. The relative impact was substantially greater for women than for men. For each of the cardiovascular diseases (CVD), morbidity and mortality were higher for diabetic women than for nondiabetic men. After adjustment for other associated risk factors, the relative impact of diabetes on CHD, IC, or stroke incidence was the same for women as for men; for CVD death and CHF, it was greater for women. Cardiovascular mortality was actually about as great for diabetic women as for diabetic men.
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            Genetic syndromes of severe insulin resistance.

            Insulin resistance is among the most prevalent endocrine derangements in the world, and it is closely associated with major diseases of global reach including diabetes mellitus, atherosclerosis, nonalcoholic fatty liver disease, and ovulatory dysfunction. It is most commonly found in those with obesity but may also occur in an unusually severe form in rare patients with monogenic defects. Such patients may loosely be grouped into those with primary disorders of insulin signaling and those with defects in adipose tissue development or function (lipodystrophy). The severe insulin resistance of both subgroups puts patients at risk of accelerated complications and poses severe challenges in clinical management. However, the clinical disorders produced by different genetic defects are often biochemically and clinically distinct and are associated with distinct risks of complications. This means that optimal management of affected patients should take into account the specific natural history of each condition. In clinical practice, they are often underdiagnosed, however, with low rates of identification of the underlying genetic defect, a problem compounded by confusing and overlapping nomenclature and classification. We now review recent developments in understanding of genetic forms of severe insulin resistance and/or lipodystrophy and suggest a revised classification based on growing knowledge of the underlying pathophysiology.
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              Insulin resistance as estimated by homeostasis model assessment predicts incident symptomatic cardiovascular disease in caucasian subjects from the general population: the Bruneck study.

              The purpose of this study was to evaluate whether insulin resistance is associated to cardiovascular disease (CVD) and to understand whether this association can be explained by traditional and novel CVD risk factors associated with this metabolic disorder. We examined a sample representative of the population of Bruneck, Italy (n = 919; aged 40-79 years). Insulin-resistant subjects were those with a score in the top quartile of the homeostasis model assessment (HOMA) for insulin resistance (HOMA-IR). Risk factors correlated with insulin resistance included BMI, A1C, HDL cholesterol, triglycerides, blood pressure, high-sensitivity C-reactive protein (hsCRP), fibrinogen, oxidized LDL, vascular cell adhesion molecule-1 (VCAM-1), and adiponectin. Subjects without CVD at baseline were followed up for 15 years for incident CVD, a composite end point including fatal and nonfatal myocardial infarction and stroke, transient ischemic attack, and any revascularization procedure. During follow-up, 118 subjects experienced a first symptomatic CVD event. Levels of HOMA-IR were higher at baseline among subjects who developed CVD (2.8) compared with those remaining free of CVD (2.5) (P < 0.05). Levels of HOMA-IR also were significantly correlated (P < 0.05) with most CVD risk factors we evaluated. In Cox proportional hazard models, insulin-resistant subjects had an age-, sex-, and smoking-adjusted 2.1-fold increased risk (95% CI 1.3-3.1) of incident symptomatic CVD relative to non-insulin-resistant subjects. After sequential adjustment for physical activity and classic risk factors (A1C, LDL cholesterol, and hypertension) as well as BMI, HDL cholesterol, triglycerides, and novel risk factors, including fibrinogen, oxidized LDL, hsCRP, VCAM-1, and adiponectin, the association between HOMA-IR and incident CVD remained significant and virtually unchanged (hazard ratio 2.2 [95% CI 1.4-3.6], P < 0.001). HOMA-estimated insulin resistance is associated with subsequent symptomatic CVD in the general population independently of all classic and several nontraditional risk factors. These data suggest that insulin resistance may be an important target to reduce CVD risk.
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                Author and article information

                Journal
                Mol Genet Genomic Med
                Mol Genet Genomic Med
                mgg3
                Molecular Genetics & Genomic Medicine
                Wiley Periodicals
                2324-9269
                2324-9269
                January 2014
                14 November 2013
                : 2
                : 1
                : 64-72
                Affiliations
                [1 ]Institute of Human Genetics, Western Galilee Medical Center Naharia, Israel
                [2 ]Faculty of Medicine in Galilee, Bar-Ilan University Safed, Israel
                [3 ]Department of Pediatrics, Bikur Cholim General Hospital, affiliated with the Hebrew University-Hadassah Medical School Jerusalem, Israel
                [4 ]Department of Neonatology, Western Galilee Medical Center Naharia, Israel
                [5 ]Department of Pathology, Sackler School of Medicine, Tel Aviv University Tel Aviv, Israel
                [6 ]Sherutei Briut Clalit Western Galilee District, Israel
                [7 ]Department of Obstetrics and Gynecology, Bikur Cholim General Hospital Jerusalem, Israel
                [8 ]Genetics Institute, Tel Aviv Sourasky Medical Center, Sackler School of Medicine, Tel Aviv University Tel Aviv, Israel
                Author notes
                Correspondence, Tzipora C. Falik-Zaccai, Institute of Human Genetics, Western Galilee Medical Center – Naharia, P.O. Box 21, Naharia 22100. Israel., Tel: 972-50-7887-941; Fax: 972-4-9107553;, E-mail: falikmd.genetics@ 123456gmail.com
                Article
                10.1002/mgg3.43
                3907912
                24498630
                52dc45a8-7821-4b7d-9aad-75cae810dc7e
                © 2013 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                Categories
                Original Articles

                insulin receptor.,genotype–phenotype,donohue syndrome,cardiomyopathy

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