ArticleThe Journal of biological chemistry2015
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.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 49 citations in OpenAlex.
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- Mammalian SLC39A13 promotes ER/Golgi iron transport and iron homeostasis in multiple compartments.Nature communications · 2024Article
- Animal Models, Pathogenesis, and Potential Treatment of Thoracic Aortic Aneurysm.International journal of molecular sciences · 2024Review
- Matricellular Proteins in the Homeostasis, Regeneration, and Aging of Skin.International journal of molecular sciences · 2023Review
- Extracellular matrix in skin diseases: The road to new therapies.Journal of advanced research · 2023Review
- Changes in transmural mass transport correlate with ascending thoracic aortic aneurysm diameter in a fibulin-4 E57K knockin mouse model.American journal of physiology. Heart and circulatory physiology · 2023Article
- Scaffold Guided Bone Regeneration for the Treatment of Large Segmental Defects in Long Bones.Biomedicines · 2023Review
- EMILIN1 deficiency causes arterial tortuosity with osteopenia and connects impaired elastogenesis with defective collagen fibrillogenesis.American journal of human genetics · 2022Article
- Soft-Tissue Material Properties and Mechanogenetics during Cardiovascular Development.Journal of cardiovascular development and disease · 2022Review
- Transforming Growth Factor-β and the Renin-Angiotensin System in Syndromic Thoracic Aortic Aneurysms: Implications for Treatment.Cardiovascular drugs and therapy · 2021Review
- Role of Fibulins in Embryonic Stage Development and Their Involvement in Various Diseases.Biomolecules · 2021Review
- Clinical and Molecular Delineation of Cutis Laxa Syndromes: Paradigms for Homeostasis.Advances in experimental medicine and biology · 2021Review
- Cardiac ECM: Its Epigenetic Regulation and Role in Heart Development and Repair.International journal of molecular sciences · 2020Review
- A matricellular protein fibulin-4 is essential for the activation of lysyl oxidase.Science advances · 2020Article
- The Genetics of Thoracic Aortic Aneurysms and Dissection: A Clinical Perspective.Biomolecules · 2020Review
- Elastic fibers and biomechanics of the aorta: Insights from mouse studies.Matrix biology : journal of the International Society for Matrix Biology · 2020Review
- Genes Associated with Thoracic Aortic Aneurysm and Dissection: 2019 Update and Clinical Implications.Aorta (Stamford, Conn.) · 2019Article
- Fibrillin microfibrils and elastic fibre proteins: Functional interactions and extracellular regulation of growth factors.Seminars in cell & developmental biology · 2019Review
- Genetics of the extracellular matrix in aortic aneurysmal diseases.Matrix biology : journal of the International Society for Matrix Biology · 2018Review
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Authors and funding
11 authors at 3 institutions in 1 country.
Funding
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.
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