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.
Highlights
Mutations in fibulin-4 cause autosomal recessive cutis laxa 1B, characterized by loose skin with vascular, lung, and skeletal abnormalities
We show that collagen fibrils in skin and tendon of the mutant mice are abnormal, providing the first evidence that fibulin-4 is required for the formation of elastic fibers and regulates collagen fibrillogenesis
Generation of the Fbln4 E57K Knock-in Mouse—Fibulin-4 E57K substitution is located in the beginning of the modified calcium-binding epidermal growth factor-like (cbEGF) domain (Fig. 1A)
Summary
Mutations in fibulin-4 cause autosomal recessive cutis laxa 1B, characterized by loose skin with vascular, lung, and skeletal abnormalities. 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. Fibulin-4 Knock-in Mouse Model for Recessive Cutis Laxa 1B system have been provided by the investigation of a hypomorphic Fbln mutant mouse and two independent vascular smooth muscle-specific conditional Fbln null mice [7,8,9] These Fbln mutant mice live into adulthood and develop ascending aortic aneurysm and arterial tortuosity. We show that collagen fibrils in skin and tendon of the mutant mice are abnormal, providing the first evidence that fibulin-4 is required for the formation of elastic fibers and regulates collagen fibrillogenesis
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