Loss of fibulin-4 disrupts collagen synthesis and maturation: Implications for pathology resulting from EFEMP2 mutations

Christina L. Papke, Jun Tsunezumi, Léa Jeanne Ringuette, Hideaki Nagaoka, Masahiko Terajima, Yoshito Yamashiro, Greg Urquhart, Mitsuo Yamauchi, Elaine C. Davis, Hiromi Yanagisawa

Research output: Contribution to journalArticlepeer-review

39 Scopus citations


Homozygous recessive mutations in either EFEMP2 (encoding fibulin-4) or FBLN5 (encoding fibulin-5), critical genes for elastogenesis, lead to autosomal recessive cutis laxa types 1B and 1A, respectively. Previously, fibulin-4was shown to bind lysyl oxidase (LOX), an elastin/collagen cross-linking enzyme, in vitro. Consistently, reported defects in humans with EFEMP2 mutations are more severe and broad in range than those due to FBLN5 mutations and encompass both elastin-rich and collagen-rich tissues. However, the underlying disease mechanism in EFEMP2 mutations has not been fully addressed. Here,we show that fibulin-4 is important for the integrity of aortic collagen in addition to elastin. Smooth muscle-specific Efemp2 loss in mouse (termed SMKO) resulted in altered fibrillar collagen localization with larger, poorly organized fibrils. LOX activity was decreased in Efemp2-null cells, and collagen cross-linking was diminished in SMKO aortas; however, elastin cross-linking was unaffected and the level of mature LOX was maintained to that of wild-type aortas. Proteomic screening identified multiple proteins involved in procollagen processing and maturation as potential fibulin-4-binding partners. We showed that fibulin-4 binds procollagen C-endopeptidase enhancer 1 (Pcolce), which enhances proteolytic cleavage of the procollagen C-terminal propeptide during procollagen processing. Interestingly, however, procollagen cleavage was not affected by the presence or absence of fibulin-4 in vitro. Thus, our data indicate that fibulin-4 serves as a potential scaffolding protein during collagen maturation in the extracellular space. Analysis of collagen in other tissues affected by fibulin-4 loss should further increase our understanding of underlying pathologic mechanisms in patients with EFEMP2 mutations.

Original languageEnglish
Pages (from-to)5867-5879
Number of pages13
JournalHuman Molecular Genetics
Issue number20
StatePublished - Jun 5 2015

Bibliographical note

Publisher Copyright:
© The Author 2015.

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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