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      A Heterozygous ZMPSTE24 Mutation Associated with Severe Metabolic Syndrome, Ectopic Fat Accumulation, and Dilated Cardiomyopathy

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          Abstract

          ZMPSTE24 encodes the only metalloprotease, which transforms prelamin into mature lamin A. Up to now, mutations in ZMPSTE24 have been linked to Restrictive Dermopathy (RD), Progeria or Mandibulo-Acral Dysplasia (MAD). We report here the phenotype of a patient referred for severe metabolic syndrome and cardiomyopathy, carrying a mutation in ZMPSTE24. The patient presented with a partial lipodystrophic syndrome associating hypertriglyceridemia, early onset type 2 diabetes, and android obesity with truncal and abdominal fat accumulation but without subcutaneous lipoatrophy. Other clinical features included acanthosis nigricans, liver steatosis, dilated cardiomyopathy, and high myocardial and hepatic triglycerides content. Mutated fibroblasts from the patient showed increased nuclear shape abnormalities and premature senescence as demonstrated by a decreased Population Doubling Level, an increased beta-galactosidase activity and a decreased BrdU incorporation rate. Reduced prelamin A expression by siRNA targeted toward LMNA transcripts resulted in decreased nuclear anomalies. We show here that a central obesity without subcutaneous lipoatrophy is associated with a laminopathy due to a heterozygous missense mutation in ZMPSTE24. Given the high prevalence of metabolic syndrome and android obesity in the general population, and in the absence of familial study, the causative link between mutation and phenotype cannot be formally established. Nevertheless, altered lamina architecture observed in mutated fibroblasts are responsible for premature cellular senescence and could contribute to the phenotype observed in this patient.

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          Most cited references 31

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          BEDTools: a flexible suite of utilities for comparing genomic features

          Motivation: Testing for correlations between different sets of genomic features is a fundamental task in genomics research. However, searching for overlaps between features with existing web-based methods is complicated by the massive datasets that are routinely produced with current sequencing technologies. Fast and flexible tools are therefore required to ask complex questions of these data in an efficient manner. Results: This article introduces a new software suite for the comparison, manipulation and annotation of genomic features in Browser Extensible Data (BED) and General Feature Format (GFF) format. BEDTools also supports the comparison of sequence alignments in BAM format to both BED and GFF features. The tools are extremely efficient and allow the user to compare large datasets (e.g. next-generation sequencing data) with both public and custom genome annotation tracks. BEDTools can be combined with one another as well as with standard UNIX commands, thus facilitating routine genomics tasks as well as pipelines that can quickly answer intricate questions of large genomic datasets. Availability and implementation: BEDTools was written in C++. Source code and a comprehensive user manual are freely available at http://code.google.com/p/bedtools Contact: aaronquinlan@gmail.com; imh4y@virginia.edu Supplementary information: Supplementary data are available at Bioinformatics online.
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            ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data

            High-throughput sequencing platforms are generating massive amounts of genetic variation data for diverse genomes, but it remains a challenge to pinpoint a small subset of functionally important variants. To fill these unmet needs, we developed the ANNOVAR tool to annotate single nucleotide variants (SNVs) and insertions/deletions, such as examining their functional consequence on genes, inferring cytogenetic bands, reporting functional importance scores, finding variants in conserved regions, or identifying variants reported in the 1000 Genomes Project and dbSNP. ANNOVAR can utilize annotation databases from the UCSC Genome Browser or any annotation data set conforming to Generic Feature Format version 3 (GFF3). We also illustrate a ‘variants reduction’ protocol on 4.7 million SNVs and indels from a human genome, including two causal mutations for Miller syndrome, a rare recessive disease. Through a stepwise procedure, we excluded variants that are unlikely to be causal, and identified 20 candidate genes including the causal gene. Using a desktop computer, ANNOVAR requires ∼4 min to perform gene-based annotation and ∼15 min to perform variants reduction on 4.7 million variants, making it practical to handle hundreds of human genomes in a day. ANNOVAR is freely available at http://www.openbioinformatics.org/annovar/ .
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              Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome.

              Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by features reminiscent of marked premature ageing. Here, we present evidence of mutations in lamin A (LMNA) as the cause of this disorder. The HGPS gene was initially localized to chromosome 1q by observing two cases of uniparental isodisomy of 1q-the inheritance of both copies of this material from one parent-and one case with a 6-megabase paternal interstitial deletion. Sequencing of LMNA, located in this interval and previously implicated in several other heritable disorders, revealed that 18 out of 20 classical cases of HGPS harboured an identical de novo (that is, newly arisen and not inherited) single-base substitution, G608G(GGC > GGT), within exon 11. One additional case was identified with a different substitution within the same codon. Both of these mutations result in activation of a cryptic splice site within exon 11, resulting in production of a protein product that deletes 50 amino acids near the carboxy terminus. Immunofluorescence of HGPS fibroblasts with antibodies directed against lamin A revealed that many cells show visible abnormalities of the nuclear membrane. The discovery of the molecular basis of this disease may shed light on the general phenomenon of human ageing.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Cells
                Cells
                cells
                Cells
                MDPI
                2073-4409
                25 April 2016
                June 2016
                : 5
                : 2
                Affiliations
                [1 ]Inserm UMR_S U910, Faculté de Médecine, Aix-Marseille Université, Marseille 13385, France; galant.damien@ 123456gmail.com (D.G.); camille.desgrouas@ 123456univ-amu.fr (C.D.); nicolas.levy@ 123456univ-amu.fr (N.L.); francoise.merono@ 123456univ-amu.fr (F.M.); patrice.roll@ 123456univ-amu.fr (P.R.); arnaud.lagarde@ 123456ap-hm.fr (A.L.); Nathalie.BONELLO@ 123456ap-hm.fr (N.B.-P.); Patrice.BOURGEOIS@ 123456ap-hm.fr (P.B.)
                [2 ]Inserm U1062/Inra1260, Aix-Marseille Université, Marseille 13385, France; benedicte.gaborit@ 123456ap-hm.fr (B.G.); inesabdesselam@ 123456hotmail.com (I.A.); anne.dutour@ 123456ap-hm.fr (A.D.)
                [3 ]APHM, Endocrinology, Metabolic Diseases and Nutrition, Marseille 13385, France
                [4 ]Laboratoire de Chimie Analytique, Faculté de Pharmacie, Aix-Marseille Université, Marseille 13385, France
                [5 ]CNRS, CRMBM UMR 7339, Aix-Marseille Université, Marseille 13385, France; monique.bernard@ 123456univ-amu.fr
                [6 ]APHM, CHU de la Timone, Laboratoire de Génétique Moléculaire, Marseille 13385, France
                [7 ]Institut de Myologie, UMR_S U974 INSERM-UPMC-CNRS-AIM, Paris 75013, France; c.coirault@ 123456institut-myologie.org
                [8 ]APHM, CHU de la Timone, Laboratoire de Biologie Cellulaire, Marseille 13385, France
                Author notes
                [* ]Correspondence: catherine.badens@ 123456univ-amu.fr ; Tel.: +33-491-32-49-25; Fax: +33-491-80-43-19
                Article
                cells-05-00021
                10.3390/cells5020021
                4931670
                27120622
                © 2016 by the authors; licensee MDPI, Basel, Switzerland.

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC-BY) license ( http://creativecommons.org/licenses/by/4.0/).

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