title: Modeling autosomal recessive cutis laxa type 1C in mice reveals distinct functions for Ltbp-4 isoforms.
abstract: Recent studies have revealed an important role for LTBP-4 in elastogenesis. Its mutational inactivation in humans causes autosomal recessive cutis laxa type 1C (ARCL1C), which is a severe disorder caused by defects of the elastic fiber network. Although the human gene involved in ARCL1C has been discovered based on similar elastic fiber abnormalities exhibited by mice lacking the short Ltbp-4 isoform (Ltbp4S(-/-)), the murine phenotype does not replicate ARCL1C. We therefore inactivated both Ltbp-4 isoforms in the mouse germline to model ARCL1C. Comparative analysis of Ltbp4S(-/-) and Ltbp4-null (Ltbp4(-/-)) mice identified Ltbp-4L as an important factor for elastogenesis and postnatal survival, and showed that it has distinct tissue expression patterns and specific molecular functions. We identified fibulin-4 as a previously unknown interaction partner of both Ltbp-4 isoforms and demonstrated that at least Ltbp-4L expression is essential for incorporation of fibulin-4 into the extracellular matrix (ECM). Overall, our results contribute to the current understanding of elastogenesis and provide an animal model of ARCL1C.
authors.affiliation: Center for Experimental Medicine, Medical Faculty, University of Cologne, 50931 Cologne, Germany.
authors.forename: Insa
authors.initials: I
authors.lastname: Bultmann-Mellin
authors.affiliation: Center for Experimental Medicine, Medical Faculty, University of Cologne, 50931 Cologne, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Conradi
authors.affiliation: Center for Experimental Medicine, Medical Faculty, University of Cologne, 50931 Cologne, Germany.
authors.forename: Alexandra C
authors.initials: AC
authors.lastname: Maul
authors.affiliation: Center for Experimental Medicine, Medical Faculty, University of Cologne, 50931 Cologne, Germany. Department of Pediatrics and Adolescent Medicine, Medical Faculty, University of Cologne, 50937 Cologne, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Dinger
authors.affiliation: Department of Molecular Hematology, University of Frankfurt Medical School, 60590 Frankfurt am Main, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Wempe
authors.affiliation: Center for Biochemistry, Medical Faculty, University of Cologne, 50931 Cologne, Germany.
authors.forename: Alexander P
authors.initials: AP
authors.lastname: Wohl
authors.affiliation: Center for Biochemistry, Medical Faculty, University of Cologne, 50931 Cologne, Germany. Institute for Dental Research and Oral Musculoskeletal Biology, Medical Faculty, University of Cologne, 50931 Cologne, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Imhof
authors.affiliation: Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany. Max Planck Institute for Metabolism Research, 50931 Cologne, Germany. Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany.
authors.forename: F Thomas
authors.initials: FT
authors.lastname: Wunderlich
authors.affiliation: Department of Radiology, Medical Faculty, University of Cologne, 50937 Cologne, Germany.
authors.forename: Alexander C
authors.initials: AC
authors.lastname: Bunck
authors.affiliation: Department of Pharmacology, Kansai Medical University, Osaka 570-8506, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: Research Programs Unit and Transplantation Laboratory, Haartman Institute, University of Helsinki, 00014 Helsinki, Finland.
authors.forename: Katri
authors.initials: K
authors.lastname: Koli
authors.affiliation: Institute of Cardiology and Sports Medicine, German Sport University Cologne, 50933 Cologne, Germany.
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Bloch
authors.affiliation: Department of Medicine/Cardiology, University of Bonn, 53127 Bonn, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Ghanem
authors.affiliation: Institute of Pharmacy, Martin Luther University Halle-Wittenberg, 06120 Halle (Saale), Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Heinz
authors.affiliation: Department of Molecular Hematology, University of Frankfurt Medical School, 60590 Frankfurt am Main, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: von Melchner
authors.affiliation: Center for Biochemistry, Medical Faculty, University of Cologne, 50931 Cologne, Germany. Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Sengle
authors.affiliation: Center for Experimental Medicine, Medical Faculty, University of Cologne, 50931 Cologne, Germany. anja.sterner-kock@uk-koeln.de.
authors.forename: Anja
authors.initials: A
authors.lastname: Sterner-Kock
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001011:Aorta / Q000002:abnormalities / Q000473:pathology; D006332:Cardiomegaly / Q000150:complications / Q000473:pathology; D003483:Cutis Laxa / Q000235:genetics* / Q000473:pathology*; D004547:Elastic Tissue / Q000378:metabolism; D004549:Elastin / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005260:Female; D020868:Gene Silencing; D005808:Genes, Recessive; D006031:Glycosylation; D006352:Heart Ventricles / Q000473:pathology; D006801:Humans; D053779:Latent TGF-beta Binding Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D008168:Lung / Q000002:abnormalities / Q000473:pathology; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D011485:Protein Binding; D020033:Protein Isoforms / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000473:pathology; D015431:Weight Loss
chemical_list: C403672:EFEMP2 protein, human; D016326:Extracellular Matrix Proteins; C538753:LTBP-4 protein, mouse; D053779:Latent TGF-beta Binding Proteins; D020033:Protein Isoforms; D004549:Elastin
keywords: ARCL1C; Autosomal recessive cutis laxa type 1C; ECM; Elastogenesis; Extracellular matrix; Fibulin-4; Fibulin-5; Latent transforming growth factor β-binding protein 4; Ltbp-4; Ltbp-4L; Ltbp-4S