The Elastic Fiber and Elastin-related Diseases
Robert P. Mecham, Ph.D
The extracellular matrix protein elastin is found in tissues that undergo stretch and require elastic recoil. It appeared in evolution concurrent with the closed circulatory system and allowed the heart to evolve into an efficient multi-chambered pump. In a similar way, elastin enabled the vertebrate lung to become a more efficient gas exchange organ by allowing the respiratory apparatus to store potential energy created by contraction of the diaphragm during inhalation and use that energy to drive lung recoil during exhalation (1). Elastic fiber assembly occurs on the cell surface and in the extracellular matrix where tropoelastin, the soluble, secreted form of elastin, interacts with microfibrils, the fibulins, and lysyl oxidase to form the functional crosslinked elastic polymer.
Mutations in elastic fiber genes adversely affect multiple organ systems, which reflect the widespread distribution of these proteins. Mutations in fibrillin-1 and fibrillin-2, for example, have been linked to Marfan syndrome and congenital contractural arachnodactyly, respectively. While fibrillin-3 is not as well characterized as the other fibrillins, recent evidence suggests that fib-3 mutations are associated with polycystic ovary syndrome. Fibrillins covalently bind the large latent form of TGF and proBMPs. Characterization of pathological mechanisms underlying fibrillin-related diseases suggest that a major function of the microfibril is to regulate TGF growth factor activity. The concept now generally accepted from this work is that phenotypes associated with fibrillin mutations result from misregulated TGF signaling.
Fibrillin forms the structural core of microfibrils, but other proteins associate with fibrillin and modify microfibril function. The microfibril-associated glycoprotein 1 (MAGP-1) is a small molecular weight protein that binds to fibrillin and is considered to be a constitutive component of microfibrils in vertebrates. Like fibrillin, MAGP1 interacts with TGF but binds the active, not the latent, form of the growth factor. Mice lacking MAGP1 have an age-dependent osteopenia due to an increased number of osteoclasts, obesity, impaired wound healing, a bleeding defect, and monocytopenia, among others. In all of these phenotypes, changes in TGFβ and macrophage number or monocyte/macrophage differentiation have been implicated in the tissue changes that occur. No human diseases have yet been directly linked to MAGP1, but its gene resides in a region of chromosome 1 with QTLs for bone mineral density, COPD, and obesity—traits that are evident when MAGP1 is deleted in mice. Mutations in the elastin gene (ELN) generally fall into two disease classes. Loss of function mutations, such as premature stop mutations, large intragenic deletions, and complete gene deletion, lead to supravalvular aortic stenosis (SVAS), an autosomal dominant disease that predominantly affects the large elastic vessels in the vascular system. A second class of elastin mutation is linked to an autosomal dominant form of cutis laxa (ADCL) and arises from nucleotide deletion, insertion, or exon-splicing errors. These mutations produce missense sequence, usually in the 3’ end of the transcript that encodes the sequences important for fiber assembly and elastin function. Using a mouse expressing the human elastin gene, we showed that alternative splicing and tissue-specific elastin misassembly act as biological modifiers of ADCL disease pathogenesis. We also found that ADCL-mutant elastin is incorporated into elastic fibers in the skin and lung with adverse effects on tissue function. In contrast, only low levels of mutant protein are incorporated into aortic elastin, which explains why the vasculature is relatively unaffected in ADCL.