Fibulin-4 E57K Knock-in Mice Recapitulate Cutaneous, Vascular and Skeletal Defects of Recessive Cutis Laxa 1B with both Elastic Fiber and Collagen Fibril Abnormalities.

Item request has been placed! ×
Item request cannot be made. ×
loading   Processing Request
Read More Add to Saved list
  • Additional Information
    • Source:
      Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1083-351X (Electronic) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE
    • Publication Information:
      Publication: 2021- : [New York, NY] : Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology
      Original Publication: Baltimore, MD : American Society for Biochemistry and Molecular Biology
    • Subject Terms:
      Gene Knock-In Techniques*; Blood Vessels/*abnormalities ; Bone and Bones/*abnormalities ; Collagen Type I/*metabolism ; Cutis Laxa/*pathology ; Elastic Tissue/*abnormalities ; Extracellular Matrix Proteins/*genetics ; Skin/*pathology; Amino Acid Sequence ; Amino Acid Substitution ; Animals ; Base Sequence ; Blood Vessels/pathology ; Bone and Bones/pathology ; Collagen Type I/ultrastructure ; Cross-Linking Reagents/metabolism ; Cutis Laxa/metabolism ; Disease Models, Animal ; Elastic Tissue/pathology ; Elastic Tissue/ultrastructure ; Extracellular Matrix Proteins/chemistry ; Extracellular Matrix Proteins/metabolism ; Fibroblasts/enzymology ; Fibroblasts/pathology ; Forelimb/abnormalities ; Forelimb/diagnostic imaging ; Forelimb/pathology ; HEK293 Cells ; Humans ; Mice, Inbred C57BL ; Models, Biological ; Molecular Sequence Data ; Mutation ; Protein Biosynthesis ; Protein Multimerization ; Protein-Lysine 6-Oxidase/metabolism ; Radiography ; Tendons/abnormalities ; Tendons/pathology ; Tendons/ultrastructure
    • Abstract:
      Fibulin-4 is an extracellular matrix protein essential for elastic fiber formation. Frameshift and missense mutations in the fibulin-4 gene (EFEMP2/FBLN4) cause autosomal recessive cutis laxa (ARCL) 1B, characterized by loose skin, aortic aneurysm, arterial tortuosity, lung emphysema, and skeletal abnormalities. Homozygous missense mutations in FBLN4 are a prevalent cause of ARCL 1B. Here we generated a knock-in mouse strain bearing a recurrent fibulin-4 E57K homozygous missense mutation. The mutant mice survived into adulthood and displayed abnormalities in multiple organ systems, including loose skin, bent forelimb, aortic aneurysm, tortuous artery, and pulmonary emphysema. Biochemical studies of dermal fibroblasts showed that fibulin-4 E57K mutant protein was produced but was prone to dimer formation and inefficiently secreted, thereby triggering an endoplasmic reticulum stress response. Immunohistochemistry detected a low level of fibulin-4 E57K protein in the knock-in skin along with altered expression of selected elastic fiber components. Processing of a precursor to mature lysyl oxidase, an enzyme involved in cross-linking of elastin and collagen, was compromised. The knock-in skin had a reduced level of desmosine, an elastin-specific cross-link compound, and ultrastructurally abnormal elastic fibers. Surprisingly, structurally aberrant collagen fibrils and altered organization into fibers were characteristics of the knock-in dermis and forelimb tendons. Type I collagen extracted from the knock-in skin had decreased amounts of covalent intermolecular cross-links, which could contribute to the collagen fibril abnormalities. Our studies provide the first evidence that fibulin-4 plays a role in regulating collagen fibril assembly and offer a preclinical platform for developing treatments for ARCL 1B.
      (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)
    • References:
      Am J Pathol. 2005 Oct;167(4):927-36. (PMID: 16192629)
      Int J Biochem Cell Biol. 2010 Jul;42(7):1084-93. (PMID: 20236620)
      J Immunol. 2006 Mar 1;176(5):3196-204. (PMID: 16493080)
      Am J Hum Genet. 2006 Jun;78(6):1075-80. (PMID: 16685658)
      Cell Mol Life Sci. 2006 Oct;63(19-20):2304-16. (PMID: 16909208)
      Circ Res. 2007 Mar 16;100(5):738-46. (PMID: 17293478)
      Circulation. 2012 Dec 4;126(23):2764-8. (PMID: 23212998)
      Exp Dermatol. 2013 Feb;22(2):88-92. (PMID: 23088642)
      Proc Natl Acad Sci U S A. 2013 Feb 19;110(8):2852-7. (PMID: 23382201)
      Orphanet J Rare Dis. 2012;7:61. (PMID: 22943132)
      Circ Res. 2010 Feb 19;106(3):583-92. (PMID: 20019329)
      J Biol Chem. 2015 Jun 26;290(26):16440-50. (PMID: 25979340)
      Eur J Hum Genet. 2010 Aug;18(8):895-901. (PMID: 20389311)
      BMC Dev Biol. 2008;8:25. (PMID: 18312615)
      Matrix Biol. 2009 May;28(4):211-20. (PMID: 19321153)
      J Biol Chem. 2009 Jun 19;284(25):16872-81. (PMID: 19349279)
      J Biol Chem. 2009 Sep 4;284(36):24553-67. (PMID: 19570982)
      Curr Opin Cell Biol. 2009 Oct;21(5):616-22. (PMID: 19525102)
      Clin Genet. 2009 Sep;76(3):276-81. (PMID: 19664000)
      Proc Natl Acad Sci U S A. 2009 Nov 10;106(45):19029-34. (PMID: 19855011)
      J Cell Sci. 2010 Sep 1;123(Pt 17):3006-18. (PMID: 20699357)
      Matrix Biol. 1999 Oct;18(5):469-80. (PMID: 10601734)
      FEBS Lett. 2001 Jan 26;489(1):59-66. (PMID: 11231014)
      Nature. 2002 Jan 10;415(6868):168-71. (PMID: 11805834)
      Nature. 2002 Jan 10;415(6868):171-5. (PMID: 11805835)
      J Biol Chem. 2003 Apr 18;278(16):14387-93. (PMID: 12473682)
      J Biol Chem. 1996 Mar 22;271(12):7113-9. (PMID: 8636146)
      J Invest Dermatol. 2005 Jan;124(1):22-7. (PMID: 15654949)
      J Biol Chem. 2007 Mar 23;282(12):8935-46. (PMID: 17255108)
      J Biol Chem. 2007 Apr 20;282(16):11805-16. (PMID: 17324935)
      FEBS Lett. 2007 Jul 31;581(19):3641-51. (PMID: 17481612)
      Am J Med Genet A. 2007 Nov 15;143A(22):2635-41. (PMID: 17937443)
      Mol Cell Biol. 2008 Feb;28(3):1061-7. (PMID: 18070922)
      Gend Med. 2007 Dec;4(4):308-28. (PMID: 18215723)
      Birth Defects Res C Embryo Today. 2007 Dec;81(4):229-40. (PMID: 18228265)
      Matrix Biol. 2011 Jan;30(1):53-61. (PMID: 20951202)
      Am J Cardiol. 2012 Jun 1;109(11):1677-80. (PMID: 22440127)
      Pediatr Dev Pathol. 2012 Mar-Apr;15(2):137-41. (PMID: 22070778)
      Mol Vis. 2012;18:2182-9. (PMID: 22919265)
      Am J Med Genet A. 2013 May;161A(5):1148-53. (PMID: 23532871)
      Biomech Model Mechanobiol. 2013 Jun;12(3):497-510. (PMID: 22790326)
      J Clin Endocrinol Metab. 2013 Aug;98(8):3095-103. (PMID: 23771926)
      Matrix Biol. 2014 Jan;33:16-22. (PMID: 23954411)
      Eur J Pediatr. 2014 May;173(5):671-5. (PMID: 24276535)
      Nat Med. 2014 Jun;20(6):670-5. (PMID: 24793237)
      PLoS Genet. 2014 Jun;10(6):e1004465. (PMID: 24968150)
      Matrix Biol. 2014 Jul;37:142-9. (PMID: 24613575)
      PLoS One. 2014;9(9):e106054. (PMID: 25255451)
      Mol Cell Biol. 2006 Mar;26(5):1700-9. (PMID: 16478991)
    • Grant Information:
      AR056523 United States AR NIAMS NIH HHS; R01 HL105314 United States HL NHLBI NIH HHS; HL53325 United States HL NHLBI NIH HHS; HL105314 United States HL NHLBI NIH HHS; R37 HL053325 United States HL NHLBI NIH HHS; R01 HL053325 United States HL NHLBI NIH HHS; R21 AR056523 United States AR NIAMS NIH HHS; AR044745 United States AR NIAMS NIH HHS; R01 AR044745 United States AR NIAMS NIH HHS
    • Contributed Indexing:
      Keywords: aneurysm; aorta; collagen; connective tissue; elastin; extracellular matrix; forelimb; lysyl oxidase; skin; tendon
    • Accession Number:
      0 (Collagen Type I)
      0 (Cross-Linking Reagents)
      0 (EFEMP2 protein, human)
      0 (Extracellular Matrix Proteins)
      EC 1.4.3.13 (Protein-Lysine 6-Oxidase)
    • Subject Terms:
      Cutis Laxa, Autosomal Recessive, Type I
    • Publication Date:
      Date Created: 20150717 Date Completed: 20151120 Latest Revision: 20210311
    • Publication Date:
      20221213
    • Accession Number:
      PMC4571872
    • Accession Number:
      10.1074/jbc.M115.640425
    • Accession Number:
      26178373