Comprehensive Clinical and Molecular Analysis of 12 Families with Type 1 Recessive Cutis Laxa
2012; Wiley; Volume: 34; Issue: 1 Linguagem: Inglês
10.1002/humu.22165
ISSN1098-1004
AutoresBert Callewaert, Chi-Ting Su, Tim Van Damme, Philip Vlummens, Fransiska Malfait, Olivier Vanakker, Bianca Schulz, Meghan Mac Neal, Elaine C. Davis, Joseph G. H. Lee, Aïcha Salhi, Sheila Unger, Ketil Heimdal, Salomé de Almeida, Uwe Kornak, Harald Gaspar, J. Bresson, Katrina Prescott, Maria E. Gosendi, Sahar Mansour, Gérald Pierard, Suneeta Madan‐Khetarpal, Frank C. Sciurba, Sofie Symoens, Paul Coucke, Lionel Van Maldergem, Zsolt Urbán, Anne De Paepe,
Tópico(s)Congenital limb and hand anomalies
ResumoHuman MutationVolume 34, Issue 1 p. 111-121 Research Article Comprehensive Clinical and Molecular Analysis of 12 Families with Type 1 Recessive Cutis Laxa Bert Callewaert, Corresponding Author Bert Callewaert Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium These two authors contributed equally to this work. Correspondence to: Bert Callewaert, Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium. E-mail: [email protected]Search for more papers by this authorChi-Ting Su, Chi-Ting Su Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania These two authors contributed equally to this work.Search for more papers by this authorTim Van Damme, Tim Van Damme Center for Medical Genetics, Ghent University Hospital, Ghent, BelgiumSearch for more papers by this authorPhilip Vlummens, Philip Vlummens Center for Medical Genetics, Ghent University Hospital, Ghent, BelgiumSearch for more papers by this authorFransiska Malfait, Fransiska Malfait Center for Medical Genetics, Ghent University Hospital, Ghent, BelgiumSearch for more papers by this authorOlivier Vanakker, Olivier Vanakker Center for Medical Genetics, Ghent University Hospital, Ghent, BelgiumSearch for more papers by this authorBianca Schulz, Bianca Schulz Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PennsylvaniaSearch for more papers by this authorMeghan Mac Neal, Meghan Mac Neal Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PennsylvaniaSearch for more papers by this authorElaine C. Davis, Elaine C. Davis Department of Anatomy and Cell Biology, McGill University, Montreal, CanadaSearch for more papers by this authorJoseph G.H. Lee, Joseph G.H. Lee Department of Anatomy and Cell Biology, McGill University, Montreal, CanadaSearch for more papers by this authorAicha Salhi, Aicha Salhi Department of Dermatology, Faculty of Medicine, Alger, AlgeriaSearch for more papers by this authorSheila Unger, Sheila Unger Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois, Lausanne, SwitzerlandSearch for more papers by this authorKetil Heimdal, Ketil Heimdal Department of Medical Genetics, Oslo University Hospital, Olso, NorwaySearch for more papers by this authorSalome De Almeida, Salome De Almeida Department of Medical Genetics, Hospitals Civis De Lisboa, Lisboa, PortugalSearch for more papers by this authorUwe Kornak, Uwe Kornak Charité, Campus Virchow-Klinikum, Berlin, GermanySearch for more papers by this authorHarald Gaspar, Harald Gaspar Institute of Human Genetics, Heidelberg University, Heidelberg, GermanySearch for more papers by this authorJean-Luc Bresson, Jean-Luc Bresson Service de Génétique, CHU Saint-Jacques, Besançon, FranceSearch for more papers by this authorKatrina Prescott, Katrina Prescott Department of Clinical Genetics, Chapel Allerton Hospital, Leeds, UKSearch for more papers by this authorMaria E. Gosendi, Maria E. Gosendi Department of Pediatrics, General Hospital of Llerenda, Badajoz, SpainSearch for more papers by this authorSahar Mansour, Sahar Mansour Department of Clinical genetics, St George's University of London, London, UKSearch for more papers by this authorGérald E. Piérard, Gérald E. Piérard Department of Dermatopathology University Hospital of Liège, Liège, BelgiumSearch for more papers by this authorSuneeta Madan-Khetarpal, Suneeta Madan-Khetarpal Division of Medical Genetics, Department of Pediatrics, Children's Hospital of Pittsburgh, PennsylvaniaSearch for more papers by this authorFrank C. Sciurba, Frank C. Sciurba Division of Pulmonary and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PennsylvaniaSearch for more papers by this authorSofie Symoens, Sofie Symoens Center for Medical Genetics, Ghent University Hospital, Ghent, BelgiumSearch for more papers by this authorPaul J Coucke, Paul J Coucke Center for Medical Genetics, Ghent University Hospital, Ghent, BelgiumSearch for more papers by this authorLionel Van Maldergem, Lionel Van Maldergem Centre de Génétique Humaine, Université de Franche-Comté, Besançon, FranceSearch for more papers by this authorZsolt Urban, Zsolt Urban Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania These two authors contributed equally to this work.Search for more papers by this authorAnne De Paepe, Anne De Paepe Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium These two authors contributed equally to this work.Search for more papers by this author Bert Callewaert, Corresponding Author Bert Callewaert Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium These two authors contributed equally to this work. Correspondence to: Bert Callewaert, Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium. E-mail: [email protected]Search for more papers by this authorChi-Ting Su, Chi-Ting Su Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania These two authors contributed equally to this work.Search for more papers by this authorTim Van Damme, Tim Van Damme Center for Medical Genetics, Ghent University Hospital, Ghent, BelgiumSearch for more papers by this authorPhilip Vlummens, Philip Vlummens Center for Medical Genetics, Ghent University Hospital, Ghent, BelgiumSearch for more papers by this authorFransiska Malfait, Fransiska Malfait Center for Medical Genetics, Ghent University Hospital, Ghent, BelgiumSearch for more papers by this authorOlivier Vanakker, Olivier Vanakker Center for Medical Genetics, Ghent University Hospital, Ghent, BelgiumSearch for more papers by this authorBianca Schulz, Bianca Schulz Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PennsylvaniaSearch for more papers by this authorMeghan Mac Neal, Meghan Mac Neal Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PennsylvaniaSearch for more papers by this authorElaine C. Davis, Elaine C. Davis Department of Anatomy and Cell Biology, McGill University, Montreal, CanadaSearch for more papers by this authorJoseph G.H. Lee, Joseph G.H. Lee Department of Anatomy and Cell Biology, McGill University, Montreal, CanadaSearch for more papers by this authorAicha Salhi, Aicha Salhi Department of Dermatology, Faculty of Medicine, Alger, AlgeriaSearch for more papers by this authorSheila Unger, Sheila Unger Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois, Lausanne, SwitzerlandSearch for more papers by this authorKetil Heimdal, Ketil Heimdal Department of Medical Genetics, Oslo University Hospital, Olso, NorwaySearch for more papers by this authorSalome De Almeida, Salome De Almeida Department of Medical Genetics, Hospitals Civis De Lisboa, Lisboa, PortugalSearch for more papers by this authorUwe Kornak, Uwe Kornak Charité, Campus Virchow-Klinikum, Berlin, GermanySearch for more papers by this authorHarald Gaspar, Harald Gaspar Institute of Human Genetics, Heidelberg University, Heidelberg, GermanySearch for more papers by this authorJean-Luc Bresson, Jean-Luc Bresson Service de Génétique, CHU Saint-Jacques, Besançon, FranceSearch for more papers by this authorKatrina Prescott, Katrina Prescott Department of Clinical Genetics, Chapel Allerton Hospital, Leeds, UKSearch for more papers by this authorMaria E. Gosendi, Maria E. Gosendi Department of Pediatrics, General Hospital of Llerenda, Badajoz, SpainSearch for more papers by this authorSahar Mansour, Sahar Mansour Department of Clinical genetics, St George's University of London, London, UKSearch for more papers by this authorGérald E. Piérard, Gérald E. Piérard Department of Dermatopathology University Hospital of Liège, Liège, BelgiumSearch for more papers by this authorSuneeta Madan-Khetarpal, Suneeta Madan-Khetarpal Division of Medical Genetics, Department of Pediatrics, Children's Hospital of Pittsburgh, PennsylvaniaSearch for more papers by this authorFrank C. Sciurba, Frank C. Sciurba Division of Pulmonary and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PennsylvaniaSearch for more papers by this authorSofie Symoens, Sofie Symoens Center for Medical Genetics, Ghent University Hospital, Ghent, BelgiumSearch for more papers by this authorPaul J Coucke, Paul J Coucke Center for Medical Genetics, Ghent University Hospital, Ghent, BelgiumSearch for more papers by this authorLionel Van Maldergem, Lionel Van Maldergem Centre de Génétique Humaine, Université de Franche-Comté, Besançon, FranceSearch for more papers by this authorZsolt Urban, Zsolt Urban Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania These two authors contributed equally to this work.Search for more papers by this authorAnne De Paepe, Anne De Paepe Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium These two authors contributed equally to this work.Search for more papers by this author First published: 24 July 2012 https://doi.org/10.1002/humu.22165Citations: 57 Communicated by Peter H. Byers Contract grant sponsors: Methusalem grant from the Ghent University (BOF 08/01M01108 to A.D.P.); National Institutes of Health (RO1 HL090648 to Z.U., P50 HL 084948 to F.C.S., and UL1 RR024153 to the University of Pittsburgh Clinical and Translational Science Institute); Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Yun-Lin branch, Taiwan (to C.T.S.); Fund for Scientific Research—Flanders (postdoctoral fellowship to B.C. and F.M.); BOF research fellowship from the Ghent University (to O.V.) Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Abstract Autosomal recessive cutis laxa type I (ARCL type I) is characterized by generalized cutis laxa with pulmonary emphysema and/or vascular complications. Rarely, mutations can be identified in FBLN4 or FBLN5. Recently, LTBP4 mutations have been implicated in a similar phenotype. Studying FBLN4, FBLN5, and LTBP4 in 12 families with ARCL type I, we found bi-allelic FBLN5 mutations in two probands, whereas nine probands harbored biallelic mutations in LTBP4. FBLN5 and LTBP4 mutations cause a very similar phenotype associated with severe pulmonary emphysema, in the absence of vascular tortuosity or aneurysms. Gastrointestinal and genitourinary tract involvement seems to be more severe in patients with LTBP4 mutations. Functional studies showed that most premature termination mutations in LTBP4 result in severely reduced mRNA and protein levels. This correlated with increased transforming growth factor-beta (TGFβ) activity. However, one mutation, c.4127dupC, escaped nonsense-mediated decay. The corresponding mutant protein (p.Arg1377Alafs*27) showed reduced colocalization with fibronectin, leading to an abnormal morphology of microfibrils in fibroblast cultures, while retaining normal TGFβ activity. We conclude that LTBP4 mutations cause disease through both loss of function and gain of function mechanisms. References Abe M, Harpel JG, Metz CN, Nunes I, Loskutoff DJ, Rifkin DB. 1994. 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Filename Description humu22165-sup-0001-FigureS1.pdf1.1 MB Supplementary Figure Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. Volume34, Issue1January 2013Pages 111-121 ReferencesRelatedInformation
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