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), and is associated with variable involvement of other organs. Both acquired and inherited forms of CL exist and the latter show extensive locus heterogeneity and congenital onset. The main histopathologic and ultrastructural anomalies in the skin of patients with CL are paucity, fragmentation, or disorganization of the dermal elastic fibers (Figure 1a ). Studies of inherited forms of CL have uncovered a growing network of genes (Table 1). On the basis of congenital nature of most inherited forms of CL, these genes are necessary for elastic fiber biogenesis and are distinct from genes involved in the homeostatic maintenance such as those inhibiting ectopic calcification of the elastic fibers (
). In the skin, they are organized in horizontally undulating deep dermal elastic fibers (Figure 1b, arrowhead), connected to thinner, vertical elaunin fibers, which show a candelabra-like branching pattern toward the dermal–epidermal junction (Figure 1b, arrow). The elaunin fibers further branch and terminate in oxytalan fibers, which are composed mostly of microfibrils and anchor the network to the dermal side of the basement membrane. The skin phenotype of patients with CL suggests that the elastic fiber system is not required for the anchoring of the epidermis to the dermis (which is disrupted in blistering diseases) (
), but rather appears to couple the growth of the skin to the rest of the body.
Molecular Basis of CL
Studies on X-linked CL provided the first insight in to the molecular basis of this disease by showing reduced activity of lysyl oxidase, an enzyme required of the cross-linking of both elastin and collagens (
Autosomal recessive CL type 1 (ARCL1) is a disease with high infantile and childhood mortality because of severe developmental emphysema or vascular defects. The identification of all three genes responsible for ARCL1 was greatly aided by the similarity in phenotype to knockout mouse models. ARCL1A associated with arterial tortuosity, aneurysms, and bone fragility is caused by mutations in fibulin-4 (FBLN4/EFEMP2) (
), and may provide a useful therapeutic target in the future.
ARCL type 2 (ARCL2) and related syndromes are associated with growth and developmental delay. Positional cloning of several causative genes has uncovered intracellular molecular pathways previously not connected to elastic fiber biogenesis. ARCL2A, characterized by abnormal glycosylation of serum proteins, is a result of mutations in the ATP6V0A2 gene, encoding the A2 subunit of the vesicular proton pump (
Patients with ARCL2B have triangular face and prematurely aged appearance and carry mutations in the pyrroline-5-carboxylate reductase (PYCR1) gene, encoding a mitochondrial enzyme involved in the proline biosynthetic pathway (
De Barsy syndrome is an autosomal recessive disease overlapping with the ARCL2 phenotype, but distinguished by the presence of corneal opacities and cataracts. Mutations in ATP6V0A2 (Kornaket al., 2008), PYCR1 (
), which encodes a binding partner of the Rab6 guanosine triphosphatase involved in vesicular trafficking. Finally, CL with macrocephaly, alopecia, and scoliosis is a recessive disease linked to mutations in the RIN2 gene (
), encoding a interactor of the Rab5 guanosine triphosphatase, another small G protein required for vesicle sorting and trafficking.
These gene identification studies have highlighted the essential role of the secretory pathway in elastic fiber biogenesis. For example, the secretion of the elastin precursor, tropoelastin, is impaired in cells with ATP6V0A2 mutations leading to accumulation of tropoelastin in Golgi vesicles (
). These discoveries support the emerging notion that appropriate intracellular sorting and routing of individual elastic fiber proteins, or groups of proteins are essential for normal extracellular fiber assembly. Whether preassembly (or microassembly) of these components occurs in particular secretory compartments will be an interesting question to address.
Another surprising set of molecules implicated in elastogenesis are mitochondrial enzymes of the proline biosynthesis pathway. Both elastin and collagens are proline-rich proteins, and thus their synthesis may be particularly sensitive to the availability of this amino acid. However, not all disease-causing ALDH18A1 mutations affect the flux through the proline biosynthetic pathway (
), suggesting that this enzyme, and by extension possibly PYCR1 as well, may have another function more relevant to the disease mechanism. Discovery of how mitochondrial and secretory proteins orchestrate an intracellular milieu conducive to elastic fiber assembly in the extracellular space will open up exciting novel areas of research and new avenues for interventions to treat disorders of the elastic fiber system.
The phenotypes and associated molecular defects in CL highlight the integration of molecular networks required for elastic fiber biogenesis with pathways associated with other structural skin disorders. Several forms of CL show joint laxity, a hallmark of Ehlers—Danlos syndrome (Byers and Murray,
2012), and RIN2 mutations result in a phenotype that appears to be intermediate between CL and Ehlers—Danlos syndrome (