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The Complexity of Elastic Fiber Biogenesis: The Paradigm of Cutis Laxa

      Introduction

      Cutis laxa (CL) is a skin disorder characterized by prematurely redundant, pendulous, inelastic, and wrinkled skin (
      • Berk D.R.
      • Bentley D.D.
      • Bayliss S.J.
      • et al.
      Cutis laxa: a review.
      ), 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 (
      • Li Q.
      • Uitto J.
      Heritable ectopic mineralization disorders: the paradigm of pseudoxanthoma elasticum.
      ).
      Figure thumbnail gr1
      Figure 1Elastic fiber abnormalities in cutis laxa. Hart’s elastin stain of a skin biopsy specimen from (a) a patient with ARCL1C/URDS caused by a homozygous mutation in LTBP4, and from (b) a normal control individual. Deep dermal elastic fibers (arrowhead) are diminished and show altered staining in the patient. The elastic fibers in the superficial dermis are missing in the patient but are present in the normal control (arrow). Magnification bars: 20 μm.
      Reproduced from (
      • Urban Z.
      • Hucthagowder V.
      • Schurmann N.
      • et al.
      Mutations in LTBP4 cause a syndrome of impaired pulmonary, gastrointestinal, genitourinary, musculoskeletal, and dermal development.
      ).
      Table 1Genes for cutis laxa and related conditions
      DiseaseDistinguishing clinical featuresMutated genes
      ADCLPulmonary and cardiovascular manifestations absent, milder or later onsetELN
      ARCL1AArterial tortuosity, lethal pulmonary hypertension, bone fragilityFBLN4/EFEMP2
      ARCL1BSupravalvular aortic stenosis, lethal developmental emphysemaFBLN5
      ARCL1C/URDSSevere gastrointestinal and urinary malformations, lethal developmental emphysema mild cardiovascular involvementLTBP4
      ARCL2AGrowth and developmental delay, abnormal glycosylation of serum proteinsATP6V0A2
      ARCL2BGrowth and developmental delay, triangular face, normal glycosylationPYCR1
      XLCLOccipital exostoses, pili tortiATP7A
      DBS/ARCL3Corneal clouding, athetoid movementsATP6V0A2, PYCR1, ALDH18A1
      GOBone fragility, short statureGORAB
      MACSMacrocephaly, alopecia, scoliosisRIN2
      Abbreviations: ADCL, autosomal dominant cutis laxa; ARCL, autosomal recessive cutis laxa; ATS, arterial tortuosity syndrome; DBS, DeBarsy syndrome; GO, geroderma osteodysplastica; MACS, macrocephaly-alopecia-cutis laxa-scoliosis syndrome; URDS, Urban-Rifkin-Davis syndrome; XLCL, X-linked cutis laxa.

      Elastic Fiber Network

      The elastic fibers consist of microfibrils, elastin, and associated proteins, and show tissue-specific organization (
      • Kielty C.M.
      Elastic fibres in health and disease.
      ). 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) (
      • Bruckner-Tuderman L.
      • Has C.
      Molecular heterogeneity of blistering disorders: the paradigm of epidermolysis bullosa.
      ), 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 (
      • Byers P.H.
      • Siegel R.C.
      • Holbrook K.A.
      • et al.
      X-linked cutis laxa: defective cross-link formation in collagen due to decreased lysyl oxidase activity.
      ) (
      • Byers P.H.
      • Murray M.L.
      Heritable collagen disorders: the paradigm of the Ehlers—Danlos syndrome.
      ). X-linked CL was recognized to be identical to occipital horn syndrome, found to be allelic to Menkes disease, and to be caused by mutations in the copper transporter ATP7A (
      • Kaler S.G.
      • Gallo L.K.
      • Proud V.K.
      • et al.
      Occipital horn syndrome and a mild Menkes phenotype associated with splice site mutations at the MNK locus.
      ). The activity of lysyl oxidase and several other enzymes (tyrosinase, dopamine b-hydroxylase) is dependent on copper.
      Genes encoding known components of the elastic fibers became candidate genes for CL. First, mutations in the elastin gene (ELN) were identified in autosomal dominant CL (ADCL) (
      • Tassabehji M.
      • Metcalfe K.
      • Hurst J.
      • et al.
      An elastin gene mutation producing abnormal tropoelastin and abnormal elastic fibres in a patient with autosomal dominant cutis laxa.
      ;
      • Zhang M.C.
      • He L.
      • Giro M.
      • et al.
      Cutis laxa arising from frameshift mutations in exon 30 of the elastin gene (ELN).
      ), characterized by a relatively mild course, but sometimes associated with aortic aneurysm and pulmonary emphysema (
      • Urban Z.
      • Gao J.
      • Pope F.M.
      • et al.
      Autosomal dominant cutis laxa with severe lung disease: synthesis and matrix deposition of mutant tropoelastin.
      ,
      • Szabo Z.
      • Crepeau M.W.
      • Mitchell A.L.
      • et al.
      Aortic aneurysmal disease and cutis laxa caused by defects in the elastin gene.
      ). The ELNmutations responsible for ADCL result in a protein deficient in interacting with microfibrils but with increased self-association (
      • Callewaert B.
      • Renard M.
      • Hucthagowder V.
      • et al.
      New insights into the pathogenesis of autosomal-dominant cutis laxa with report of five ELN mutations.
      ). Incorporation of mutant elastin into the elastic fibers results in reduced compliance of tissues (
      • Hu Q.
      • Shifren A.
      • Sens C.
      • et al.
      Mechanisms of emphysema in autosomal dominant cutis laxa.
      ), consistent with a dominantnegative mechanism.
      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) (
      • Hucthagowder V.
      • Sausgruber N.
      • Kim K.H.
      • et al.
      Fibulin-4: a novel gene for an autosomal recessive cutis laxa syndrome.
      ). ARCL1B is distinguished by the presence of supravalvular aortic stenosis, and fibulin-5 (FBLN5) is mutated in affected individuals (
      • Loeys B.
      • Van Maldergem L.
      • Mortier G.
      • et al.
      Homozygosity for a missense mutation in fibulin-5 (FBLN5) results in a severe form of cutis laxa.
      ). Finally, ARCL1C, a disease with severe gastrointestinal and urinary involvement, is a result of mutations in the gene for the latent transforming growth factor-beta-binding protein 4 (LTBP4) (
      • Urban Z.
      • Hucthagowder V.
      • Schurmann N.
      • et al.
      Mutations in LTBP4 cause a syndrome of impaired pulmonary, gastrointestinal, genitourinary, musculoskeletal, and dermal development.
      ).
      All the three genes for ARCL1 (FBLN4, FBLN5, LTBP4) encode secreted, multi-adhesive proteins required for the hierarchical, cell-directed process of elastic fiber assembly (
      • Czirok A.
      • Zach J.
      • Kozel B.A.
      • et al.
      Elastic fiber macro-assembly is a hierarchical, cell motion-mediated process.
      ). Transforming growth factor-beta (TGFb) signaling is a common downstream pathway activated in ADCL (
      • Hu Q.
      • Shifren A.
      • Sens C.
      • et al.
      Mechanisms of emphysema in autosomal dominant cutis laxa.
      ,
      • Callewaert B.
      • Renard M.
      • Hucthagowder V.
      • et al.
      New insights into the pathogenesis of autosomal-dominant cutis laxa with report of five ELN mutations.
      ), ARCL1A (
      • Renard M.
      • Holm T.
      • Veith R.
      • et al.
      Altered TGFbeta signaling and cardiovascular manifestations in patients with autosomal recessive cutis laxa type I caused by fibulin-4 deficiency.
      ), and ARCL1C (
      • Urban Z.
      • Hucthagowder V.
      • Schurmann N.
      • et al.
      Mutations in LTBP4 cause a syndrome of impaired pulmonary, gastrointestinal, genitourinary, musculoskeletal, and dermal development.
      ), 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 (
      • Kornak U.
      • Reynders E.
      • Dimopoulou A.
      • et al.
      Impaired glycosylation and cutis laxa caused by mutations in the vesicular H+-ATPase subunit ATP6V0A2.
      ).
      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 (
      • Guernsey D.L.
      • Jiang H.
      • Evans S.C.
      • et al.
      Mutation in pyrroline-5-carboxylate reductase 1 gene in families with cutis laxa type 2.
      ). Mutations in this gene result in altered mitochondrial morphology and increased oxidative stress (
      • Reversade B.
      • Escande-Beillard N.
      • Dimopoulou A.
      • et al.
      Mutations in PYCR1 cause cutis laxa with progeroid features.
      ).
      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 (
      • Reversade B.
      • Escande-Beillard N.
      • Dimopoulou A.
      • et al.
      Mutations in PYCR1 cause cutis laxa with progeroid features.
      ), or the gene for Δ1-pyrroline-5-carboxylate synthase (ALDH18A1) (
      • Skidmore D.L.
      • Chitayat D.
      • Morgan T.
      • et al.
      Further expansion of the phenotypic spectrum associated with mutations in ALDH18A1, encoding Delta(1)-pyrroline-5-carboxylate synthase (P5CS).
      ), encoding another mitochondrial proline biosynthetic enzyme, have been described in patients with De Barsy syndrome.
      Gerodermia osteodysplastica is a related disease characterized by marked bone fragility and caused by recessive mutations in the GORAB gene (
      • Hennies H.C.
      • Kornak U.
      • Zhang H.
      • et al.
      Gerodermia osteodysplastica is caused by mutations in SCYL1BP1, a Rab-6 interacting golgin.
      ), 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 (
      • Basel-Vanagaite L.
      • Sarig O.
      • Hershkovitz D.
      • et al.
      RIN2 deficiency results in macrocephaly, alopecia, cutis laxa, and scoliosis: MACS syndrome.
      ), 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 (
      • Hucthagowder V.
      • Morava E.
      • Kornak U.
      • et al.
      Loss-of-function mutations in ATP6V0A2 impair vesicular trafficking, tropoelastin secretion and cell survival.
      ). Conversely, in cells with RIN2 mutations the production of microfibrils and fibulin-5 appears to be disrupted (
      • Basel-Vanagaite L.
      • Sarig O.
      • Hershkovitz D.
      • et al.
      RIN2 deficiency results in macrocephaly, alopecia, cutis laxa, and scoliosis: MACS syndrome.
      ). 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 (
      • Bicknell L.S.
      • Pitt J.
      • Aftimos S.
      • et al.
      A missense mutation in ALDH18A1, encoding Delta1-pyrroline-5-carboxylate synthase (P5CS), causes an autosomal recessive neurocutaneous syndrome.
      ), 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.

      Conclusions

      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 (
      • Syx D.
      • Malfait F.
      • Van Laer L.
      • et al.
      The RIN2 syndrome: a new autosomal recessive connective tissue disorder caused by deficiency of Ras and Rab interactor 2 (RIN2).
      ). Sparse hair has been described in several CL syndromes including patients with ELN mutations (
      • Szabo Z.
      • Crepeau M.W.
      • Mitchell A.L.
      • et al.
      Aortic aneurysmal disease and cutis laxa caused by defects in the elastin gene.
      ). Moreover, RIN2 mutations result in alopecia (
      • Basel-Vanagaite L.
      • Sarig O.
      • Hershkovitz D.
      • et al.
      RIN2 deficiency results in macrocephaly, alopecia, cutis laxa, and scoliosis: MACS syndrome.
      ). Thus, the elastic fiber system may be connected to the molecular network disrupted in structural hair disorders (
      • Harel S.
      • Christiano A.M.
      Genetics of structural hair disorders.
      ).

      Conflict of Interest

      The author states no conflict of interest.

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