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Comprehensive clinical and molecular analysis of 12 families with type 1 recessive cutis laxa.

Bert Callewaert1,Chi-Ting Su2, Tim Van Damme1, Philip Vlummens1, Fransiska Malfait1, Olivier Vanakker1, Bianca Schulz2, Meghan Mac Neal2, Elaine C. Davis3, Joseph G.H. Lee3, Aicha Salhi4, Sheila Unger5, Ketil Heimdal6, Salome De Almeida7, Uwe Kornak8, Harald Gaspar9, Jean-Luc Bresson10, Katrina Prescott11, Maria E. Gosendi12, Sahar Mansour13, Gérald E. Piérard14, Suneeta Madan-Khetarpal15, Frank C. Sciurba16, Sofie Symoens1, Paul J Coucke1, Lionel Van Maldergem17, Zsolt Urban2, and Anne De Paepe1

1-Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium; 2-Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania; 3 - Department of Anatomy and Cell Biology, McGill University, Montreal, Canada; 4 - Department of Dermatology, Faculty of Medicine, Alger, Algeria; 5 - Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; 6 - Department of Medical Genetics, Oslo University Hospital, Olso, Norway; 7 - Department of Medical Genetics, Hospitals Civis De Lisboa, Lisboa, Portugal; 8 - Charité, Campus Virchow-Klinikum, Berlin, Germany; 9 - Institute of Human Genetics, Heidelberg University, Heidelberg, Germany; 10 - Service de Génétique, CHU Saint-Jacques, Besançon, France; 11 - Department of Clinical Genetics, Chapel Allerton Hospital, Leeds, UK; 12 - Department of Pediatrics, General Hospital of Llerenda, Badajoz, Spain; 13 - Department of Clinical genetics, St George's University of London, London, UK; 14 - Department of Dermatopathology University Hospital of Liège, Liège, Belgium; 15 - Division of Medical Genetics, Department of Pediatrics, Children's Hospital of Pittsburgh, Pennsylvania; 16 - Division of Pulmonary and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; 17 - Centre de Génétique Humaine, Université de Franche-Comté, Besançon

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.