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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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      We sought to conduct a systematic review and meta-analysis of the cardiovascular risk associated with the metabolic syndrome as defined by the 2001 National Cholesterol Education Program (NCEP) and 2004 revised National Cholesterol Education Program (rNCEP) definitions. Numerous studies have investigated the cardiovascular risk associated with the NCEP and rNCEP definitions of the metabolic syndrome. There is debate regarding the prognostic significance of the metabolic syndrome for cardiovascular outcomes. We searched the Cochrane Library, EMBASE, and Medline databases through June 2009 for prospective observational studies investigating the cardiovascular effects of the metabolic syndrome. Two reviewers extracted data, which were aggregated using random-effects models. We identified 87 studies, which included 951,083 patients (NCEP: 63 studies, 497,651 patients; rNCEP: 33 studies, 453,432 patients). There was little variation between the cardiovascular risk associated with NCEP and rNCEP definitions. When both definitions were pooled, the metabolic syndrome was associated with an increased risk of cardiovascular disease (CVD) (relative risk [RR]: 2.35; 95% confidence interval [CI]: 2.02 to 2.73), CVD mortality (RR: 2.40; 95% CI: 1.87 to 3.08), all-cause mortality (RR: 1.58; 95% CI: 1.39 to 1.78), myocardial infarction (RR: 1.99; 95% CI: 1.61 to 2.46), and stroke (RR: 2.27; 95% CI: 1.80 to 2.85). Patients with the metabolic syndrome, but without diabetes, maintained a high cardiovascular risk. The metabolic syndrome is associated with a 2-fold increase in cardiovascular outcomes and a 1.5-fold increase in all-cause mortality. Studies are needed to investigate whether or not the prognostic significance of the metabolic syndrome exceeds the risk associated with the sum of its individual components. Furthermore, studies are needed to elucidate the mechanisms by which the metabolic syndrome increases cardiovascular risk. Copyright © 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
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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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          The Human Gene Mutation Database: 2008 update

          The Human Gene Mutation Database (HGMD®) is a comprehensive core collection of germline mutations in nuclear genes that underlie or are associated with human inherited disease. Here, we summarize the history of the database and its current resources. By December 2008, the database contained over 85,000 different lesions detected in 3,253 different genes, with new entries currently accumulating at a rate exceeding 9,000 per annum. Although originally established for the scientific study of mutational mechanisms in human genes, HGMD has since acquired a much broader utility for researchers, physicians, clinicians and genetic counselors as well as for companies specializing in biopharmaceuticals, bioinformatics and personalized genomics. HGMD was first made publicly available in April 1996, and a collaboration was initiated in 2006 between HGMD and BIOBASE GmbH. This cooperative agreement covers the exclusive worldwide marketing of the most up-to-date (subscription) version of HGMD, HGMD Professional, to academic, clinical and commercial users.
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            Author and article information

            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
            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
            3907912
            10.1002/mgg3.43
            © 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.

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