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

doi:10.1242/dmm.018960

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 Citationer (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.

Originalsprog	Engelsk
Tidsskrift	Disease models & mechanisms
Vol/bind	8
Udgave nummer	4
Sider (fra-til)	403-15
Antal sider	13
ISSN	1754-8403
DOI	https://doi.org/10.1242/dmm.018960
Status	Udgivet - 1 apr. 2015

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10.1242/dmm.018960

403.full.pdfForlagets udgivne version, 4,37 MBLicens: CC BY

Citationsformater

Bultmann-Mellin, I., Conradi, A., Maul, A. C., Dinger, K., Wempe, F., Wohl, A. P., Imhof, T., Wunderlich, F. T., Bunck, A. C., Nakamura, T., Koli, K., Bloch, W., Ghanem, A., Heinz, A., von Melchner, H., Sengle, G., & Sterner-Kock, A. (2015). Modeling autosomal recessive cutis laxa type 1C in mice reveals distinct functions for Ltbp-4 isoforms. Disease models & mechanisms, 8(4), 403-15. https://doi.org/10.1242/dmm.018960

Bultmann-Mellin, I, Conradi, A, Maul, AC, Dinger, K, Wempe, F, Wohl, AP, Imhof, T, Wunderlich, FT, Bunck, AC, Nakamura, T, Koli, K, Bloch, W, Ghanem, A, Heinz, A, von Melchner, H, Sengle, G & Sterner-Kock, A 2015, 'Modeling autosomal recessive cutis laxa type 1C in mice reveals distinct functions for Ltbp-4 isoforms', Disease models & mechanisms, bind 8, nr. 4, s. 403-15. https://doi.org/10.1242/dmm.018960

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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.",

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",

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

note = "{\textcopyright} 2015. Published by The Company of Biologists Ltd.",

year = "2015",

month = apr,

day = "1",

doi = "10.1242/dmm.018960",

language = "English",

volume = "8",

pages = "403--15",

journal = "Disease models & mechanisms",

issn = "1754-8403",

publisher = "company of biologists",

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TY - JOUR

T1 - Modeling autosomal recessive cutis laxa type 1C in mice reveals distinct functions for Ltbp-4 isoforms

AU - Bultmann-Mellin, Insa

AU - Conradi, Anne

AU - Maul, Alexandra C

AU - Dinger, Katharina

AU - Wempe, Frank

AU - Wohl, Alexander P

AU - Imhof, Thomas

AU - Wunderlich, F Thomas

AU - Bunck, Alexander C

AU - Nakamura, Tomoyuki

AU - Koli, Katri

AU - Bloch, Wilhelm

AU - Ghanem, Alexander

AU - Heinz, Andrea

AU - von Melchner, Harald

AU - Sengle, Gerhard

AU - Sterner-Kock, Anja

PY - 2015/4/1

Y1 - 2015/4/1

N2 - 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.

AB - 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.

KW - Animals

KW - Animals, Newborn

KW - Aorta

KW - Cardiomegaly

KW - Cutis Laxa

KW - Elastic Tissue

KW - Elastin

KW - Extracellular Matrix

KW - Extracellular Matrix Proteins

KW - Female

KW - Gene Silencing

KW - Genes, Recessive

KW - Glycosylation

KW - Heart Ventricles

KW - Humans

KW - Latent TGF-beta Binding Proteins

KW - Lung

KW - Mice, Inbred C57BL

KW - Models, Biological

KW - Protein Binding

KW - Protein Isoforms

KW - Skin

KW - Weight Loss

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1242/dmm.018960

DO - 10.1242/dmm.018960

M3 - Journal article

C2 - 25713297

SN - 1754-8403

VL - 8

SP - 403

EP - 415

JO - Disease models & mechanisms

JF - Disease models & mechanisms

IS - 4

ER -

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

Abstract

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