Modeling autosomal recessive cutis laxa type 1C in mice reveals distinct functions for Ltbp-4 isoforms

Insa Bultmann-Mellin, Anne Conradi, Alexandra C Maul, Katharina Dinger, Frank Wempe, Alexander P Wohl, Thomas Imhof, F Thomas Wunderlich, Alexander C Bunck, Tomoyuki Nakamura, Katri Koli, Wilhelm Bloch, Alexander Ghanem, Andrea Heinz, Harald von Melchner, Gerhard Sengle, Anja Sterner-Kock

    26 Citations (Scopus)

    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.

    Original languageEnglish
    JournalDisease models & mechanisms
    Volume8
    Issue number4
    Pages (from-to)403-15
    Number of pages13
    ISSN1754-8403
    DOIs
    Publication statusPublished - 1 Apr 2015

    Keywords

    • Animals
    • Animals, Newborn
    • Aorta
    • Cardiomegaly
    • Cutis Laxa
    • Elastic Tissue
    • Elastin
    • Extracellular Matrix
    • Extracellular Matrix Proteins
    • Female
    • Gene Silencing
    • Genes, Recessive
    • Glycosylation
    • Heart Ventricles
    • Humans
    • Latent TGF-beta Binding Proteins
    • Lung
    • Mice, Inbred C57BL
    • Models, Biological
    • Protein Binding
    • Protein Isoforms
    • Skin
    • Weight Loss
    • Journal Article
    • Research Support, Non-U.S. Gov't

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