cutis laxa: intersection of elastic fiber biogenesis, tgfβ signaling, the secretory pathway and...

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Matrix Biology xxx (2013) xxx–xxx

MATBIO-00980; No of Pages 7

Contents lists available at ScienceDirect

Matrix Biology

j ourna l homepage: www.e lsev ie r .com/ locate /matb io

Mini review

Cutis laxa: Intersection of elastic fiber biogenesis, TGFβ signaling, thesecretory pathway and metabolism

OFZsolt Urban a,⁎, Elaine C. Davis b

a Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, United Statesb Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, , H3A 0C7Canada

⁎ Corresponding author at: Zsolt Urban, Department oStreet, Crabtree Hall A300, Pittsburgh, PA 15261, Unitedfax: +1 412 624 3020.

E-mail address: [email protected] (Z. Urban).

0945-053X/$ – see front matter © 2013 Elsevier B.V. All rhttp://dx.doi.org/10.1016/j.matbio.2013.07.006

Please cite this article as: Urban, Z., Davis, Emetabolism, Matrix Biol. (2013), http://dx.d

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Article history:Received 24 June 2013Received in revised form 8 July 2013Accepted 9 July 2013Available online xxxx

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RCutis laxa (CL) is a disease characterized by redundant and inelastic skin displays extensive locus heterogeneity.Together with geroderma osteodysplasticum and arterial tortuosity syndrome, which show phenotypic overlapwith CL, eleven CL-related genes have been identified to date, which encode proteins within 3 groups. Elastin,fibulin-4, fibulin-5 and latent transforming growth factor-β-binding protein 4 are secreted proteins whichform elastic fibers and are involved in the sequestration and subsequent activation of transforming growthfactor-β (TGFβ). Proteins within the second group, localized to the secretory pathway, perform transport andmembrane trafficking functions necessary for the modification and secretion of elastic fiber components. Keyproteins include a subunit of the vacuolar-type proton pump,which ensures the efficient secretion of tropoelastin,the precursor or elastin. A copper transporter is required for the activity of lysyl oxidases, which crosslink collagenand elastin. A Rab6-interacting goglin recruits kinesin motors to Golgi-vesicles facilitating the transport from theGolgi to the plasma membrane. The Rab and Ras interactor 2 regulates the activity of Rab5, a small guanosinetriphosphatase essential for the endocytosis of various cell surface receptors, including integrins. Proteins of thethird group related to CL perform metabolic functions within the mitochondria, inhibiting the accumulation ofreactive oxygen species. Two of these proteins catalyze subsequent steps in the conversion of glutamate toproline. The third transports dehydroascorbate intomitochondria. Recent studies on CL-related proteins highlightthe intricate connections among membrane trafficking, metabolism, extracellular matrix assembly, and TGFβsignaling.

© 2013 Elsevier B.V. All rights reserved.

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R1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 02. CL genes in elastic fiber biogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 03. CL and TGFb signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 04. The CL proteins and TGFβ in Evolution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 05. CL and the secretory pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 06. CL and metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 07. Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

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U1. Introduction

Cutis laxa (CL) is a group of disorders characterized by redundant,pendulous, prematurely wrinkled and inelastic skin. CL can either beinherited or acquired secondary to a range of inflammatory conditions.

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.C., Cutis laxa: Intersection ooi.org/10.1016/j.matbio.2013.

Considerable progress has been made in identifying the genesresponsible for inherited forms of CL (Table 1). A detailed review ofthe clinical manifestations of the different types of inherited CL andrelated syndromes has recently been published (Berk et al., 2012).Recent reviews also discussed the genetic heterogeneity of CL and itsimplications for the complexity of elastic fiber biogenesis (Urban,2012; Uitto et al., 2013). Complementary human genetic, biochemical,cell biological and animal model studies now suggest that many formsof inherited CL display abnormalities both of elastic fibers biogenesisand of transforming growth factor-β (TGFβ) signaling, membrane

f elastic fiber biogenesis, TGFβ signaling, the secretory pathway and07.006

http://dx.doi.org/10.1016/j.matbio.2013.07.006

mailto:[email protected]


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trafficking and mitochondrial metabolism, highlighting the integrationof these processes atmultiple levels. The goal of this review is to discussthese latest insights.

2. CL genes in elastic fiber biogenesis

The skin manifestations in inherited CL are usually congenital andgeneralized, and are commonly associated with involvement of elastictissues within the respiratory and cardiovascular systems (Berk et al.,2012). The phenotype is consistent with a generalized elastinopathy.However, some forms of CL are also associated with growth and devel-opmental delay, craniofacial anomalies, reduced bone density, jointand ligament laxity, hernias and gastrointestinal and urinary tractlesions suggesting broader connective tissue involvement (Table 1).Histological and electron microscopic studies have shown a range ofelastic fiber abnormalities in CL, consistent with defective assembly ofthese extracellular matrix (ECM) structures (Fig. 1). Consistently, severalgenes that encodeproteins associatedwith elasticfibers, including elastin,fibulin-4, fibulin-5 and latent TGFβ-binding protein 4 (LTBP4), have beenidentified to harbor mutations causing CL (Table 1). The mechanisms bywhich mutations in these genes lead to abnormal elastic fiber assemblyand altered TGFβ signaling is beginning to emerge.

Autosomal dominant CL (ADCL) ismost commonly caused by frame-shift mutations within the last 5 exons of the elastin gene (ELN)(Callewaert et al., 2011; Hadj-Rabia et al., 2013). These mutationslead to the replacement of the C-terminus of the elastin precursor,tropoelastin, with a missense peptide sequence as a consequence of astable mutant mRNA and protein (Szabo et al., 2006; Callewaert et al.,2011). ADCL-causing mutations have multiple cellular and biochemicaleffects. The most upstream (exon 30) mutations result in the longestmissense peptide sequence, which activates the unfolded proteinresponse (UPR) and leads to increased rates of apoptosis both inpatient-derived skin fibroblasts (Callewaert et al., 2011) and in a trans-genic mouse model (Hu et al., 2010). Despite activation of the UPR, themutant tropoelastin is partially secreted by ADCL cells and alters theassembly of the elastic fibers by interfering with the binding oftropoelastin to fibulin-5 and fibrillin-1 (Sato et al., 2006). In addition,ADCLmutations increase the coacervation of tropoelastin in a dominantmanner (Callewaert et al., 2011). The effects of these biochemicalchanges include ultrastructural disorganization and altered mechanical

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Table 1Cutis laxa and related genes.

Diseasea Distinguishing clinical features Mutatedgenes

Gene functio

ADCL Pulmonary and cardiovascular manifestationsabsent, milder or later onset

ELN Structural pro

ARCL1A Supravalvular aortic stenosis, lethal developmentalemphysema

FBLN5 Accessory proFBN1, LOXL1

ARCL1B Arterial tortuosity, lethal pulmonary hypertension,bone fragility

FBLN4EFEMP2

Accessory proLOX and FBN

ARCL1C/URDS

Severe gastrointestinal and urinary malformations,lethal developmental emphysema mild cardiovascular involvement

LTBP4 Accessory proFN, FBN1, and

ARCL2A Growth and developmental delay, abnormalglycosylation of serum proteins

ATP6V0A2 A subunit ofacidifies vesic

ARCL2B Growth and developmental delay, triangular face,normal glycosylation

PYCR1 Mitochondriapathway

XLCL Occipital exostoses, pili torti ATP7A Copper transactivity

DBS/ARCL3

Corneal clouding, athetoid movements ALDH18A1 Mitochondriapathway

GO Bone fragility, short stature GORAB Localized to tinvolved in v

MACS Macrocephaly, alopecia, scoliosis RIN2 Localized to texchange fac

ATS Triangular face, arterial tortuosity, normal lungs SLC2A10 Transports de

a ADCL, autosomal dominant cutis laxa; ARCL, autosomal recessive cutis laxa; URDS, Urban–Rosteodysplasticum; MACS, macrocephaly alopecia cutis laxa scoliosis syndrome; ATS

Please cite this article as: Urban, Z., Davis, E.C., Cutis laxa: Intersection ometabolism, Matrix Biol. (2013), http://dx.doi.org/10.1016/j.matbio.2013.

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properties of the elastic fibers (Hu et al., 2010; Callewaert et al., 2011).In transgenic mouse models, the mutant tropoelastin was observed tocontribute to lung elastic fibers, but was largely excluded from fibersin the skin and blood vessels (Hu et al., 2010; Sugitani et al., 2012).Although these findings point to tissue-specific mechanisms of elasticfiber assembly, the precise molecular determinants of such tissue spec-ificity remain to be determined. Nevertheless, it is clear that ADCL-related ELNmutations are characterized by a complexmolecular diseasemechanismwith a gain of function in polymerization and a loss of func-tion in elastin-microfibril interaction coupled with some non-specifictoxic effects associated with protein misfolding.

The profound functional consequences of alterations at theC-terminus of tropoelastin in ADCL strengthen an existing body of evi-dence for the essential nature of this region for a variety of activities. Forexample, the last 17 amino acids of tropoelastin are key for cell attach-ment both via heparan sulfate proteoglycans (HSPGs) (Broekelmannet al., 2005) and through non-RGD-mediated αvβ3 integrin binding(Bax et al., 2009). Consistent with the dynamic, cell-mediated natureof elastic fiber assembly (Czirok et al., 2006; Kozel et al., 2006), anti-bodies against this C-terminal cell interaction domain interfere withelastin deposition (Brown-Augsburger et al., 1996). Additionally, thehydrophobic domain encoded by exon 30 is essential for tropoelastinpolymerization, and hence, fiber formation (Kozel et al., 2003).

Whereas the molecular mechanisms of ADCL are quite complex,autosomal recessive CL (ARCL) involves a simpler, loss of functionmechanism. Type 1 ARCL (ARCL1), characterized by severe cardio-vascular or pulmonary manifestations (Table 1), can be caused bymutations in fibulin-5 (FBLN5, ARCL1A) (Loeys et al., 2002), fibulin-4(FBLN4/EFEMP2, ARCL1B) (Hucthagowder et al., 2006), and LTBP4(ARCL1C) (Urban et al., 2009).

Loss of functionmutations in FBLN5 result in ARCL1A associatedwithsevere, often fatal, infantile respiratory distress related to developmen-tal emphysema. Other common manifestations include supravalvularaortic stenosis, pulmonary artery stenosis and inguinal hernias (Loeyset al., 2002; Elahi et al., 2006; Claus et al., 2008; Callewaert et al.,2013). Fibulin-5 knockout mice show a similar phenotype with skinlaxity, developmental emphysema, elongation, tortuosity and alteredbranching of the large arteries (Nakamura et al., 2002; Yanagisawaet al., 2002), an increased angiogenic phenotype (Sullivan et al., 2007),and pelvic prolapse (Drewes et al., 2007). ARCL1A-causing mutations

n References

tein of the elastic fibers (Hu et al., 2010; Callewaert et al., 2011)

tein of the elastic fibers, binds ELN,, LTBP2 and LTBP4

(Loeys et al., 2002)

tein of the elastic fibers, binds1

(Hucthagowder et al., 2006; Dasouki et al.,2007; Renard et al., 2010)

tein of the elastic fibers, binds TGFB1,FBLN5

(Urban et al., 2009)

the vacuolar-type proton pump,les in the secretory pathway

(Kornak et al., 2008; Hucthagowder et al.,2009)

l enzyme in the proline-biosynthetic (Guernsey et al., 2009; Reversade et al., 2009)

porter required for lysyl oxidase (Byers et al., 1980; Moller et al., 2005;Kennerson et al., 2010)

l enzyme in the proline-biosynthetic (Bicknell et al., 2008; Skidmore et al., 2011)

he Golgi, binds RAB6, a G-proteinesicle trafficking

(Hennies et al., 2008)

he Golgi, is a guanine nucleotidetor of RAB5

(Basel-Vanagaite et al., 2009)

hydroascorbate into mitochondria (Coucke et al., 2006; Lee et al., 2010)

ifkin–Davis syndrome; XLCL, X-linked cutis laxa; DBS, De Barsy syndrome; GO, geroderma



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Fig. 1. Electronmicroscopic analyses of elasticfibers in skin punch biopsies fromunaffected and CL patients. (A)Anunaffected individual; (B) a patientwith a heterozygousmutation in theelastin gene; (C) a patient with a homozygous mutation in the LTBP4 gene; (D) dermal elastic fibers from a patient with CL of an unknown cause. Bar = 500 nm.

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affect the folding and secretion offibulin-5 resulting in a failure of elastinto be properly integrated with microfibrils (Hu et al., 2006; Lotery et al.,2006; Choi et al., 2009). Biochemical studies have highlighted a numberof activities of fibulin-5, including its ability to bind lysyl oxidase-like-1(LOXL1) (Liu et al., 2004; Hirai et al., 2007b), LOXL2, and LOXL4 (Hiraiet al., 2007b), fibrillin-1 (Freeman et al., 2005; El-Hallous et al., 2007;Ono et al., 2009), tropoelastin (Yanagisawa et al., 2002; Hirai et al.,2007b), LTBP2 (Hirai et al., 2007a) and LTBP4 (Noda et al., 2013). Thebinding of fibulin-5 increases the coacervation and crosslinking oftropoelastin, facilitating elastic fiber formation (Hirai et al., 2007b;Wachi et al., 2008). Furthermore, an RGD motif in fibulin-5 binds αvβ3,αvβ5, α4β1, α5β1 and α9β1 integrins (Nakamura et al., 2002; Lomaset al., 2007). In vascular smoothmuscle cells (VSMC), themain integrinsresponsible for attachment to fibulin-5 are α4β1 and α5β1; however,binding to fibulin-5 does not result in integrin activation (Lomas et al.,2007). Additionally, in vivo evidence suggests that fibulin-5-integrininteractions are not necessary for elastic fiber formation, as mice carry-ing homozygous RGDNRGE mutations in fibulin-5 are normal (Budathaet al., 2011).

Fibulin-5-deficient tissues show increased angiogenesis and vascularinvasion, with elevated VEGF and angiopoietin expression playing a role(Sullivan et al., 2007). Conversely, transplanted tumors show decreasedgrowth in fibulin-5 knockout mice associated with increased reactiveoxygen species (ROS) production dependent on β1-integrin and fibro-nectin (Schluterman et al., 2010). Fibulin-5 also binds the extracellularsuperoxide dismutase, Sod3. In the absence of fibulin-5, the localizationof Sod3 to the ECM is lost, leading to an elevated extracellular super-oxide levels in vessels (Nguyen et al., 2004). However, it remainsunclear if any of these physiological changes contribute to diseasein human patients with fibulin-5 mutations.

Mutations in FBLN4 cause ARCL1B, a disease associated with wide-spread systemic involvement, including arterial tortuosity, aorticaneurysm, pulmonary hypertension, developmental emphysema,bone fragility, arachnodactyly, joint laxity and diaphragmatic andinguinal hernias (Hucthagowder et al., 2006; Dasouki et al., 2007;Hoyer et al., 2009; Renard et al., 2010). Knockout and hypomorphicmice replicate many of these phenotypes (McLaughlin et al., 2006;Hanada et al., 2007; Horiguchi et al., 2009; Huang et al., 2010).


EDFibulin-4 binds tropoelastin (McLaughlin et al., 2006), fibrillin-1 (El-

Hallous et al., 2007; Choudhury et al., 2009; Ono et al., 2009) andLTBP1 (Massam-Wu et al., 2010). A somewhat different set of ligands,distinct binding affinities for shared ligands and cell type- and develop-mental stage-specific expression of fibulin-5 and fibulin-4 ensure thatthese proteins perform non-overlapping functions in elastic fiberassembly. For example, fibulin-5 has higher affinity for tropoelastinthan fibrillin-1, whereas fibulin-4 preferentially binds fibrillin-1 overtropoelastin. Fibulin-4 can form a ternary complex with tropoelastinand LOX, facilitating the crosslinking of elastin (Choudhury et al., 2009;Horiguchi et al., 2009). In addition, fibulin-5 enhances tropoelastin coac-ervation (Hirai et al., 2007b; Wachi et al., 2008). Both fibulin-4 andfibulin-5 limit tropoelastin droplet size during the maturation of coacer-vates (Cirulis et al., 2008). In both humanmutations and animal models,the absence of fibulin-5 leads to elastin deposits that are large and notintegrated with the microfibril scaffold (Nakamura et al., 2002;Yanagisawa et al., 2002; Hu et al., 2006). In contrast, fibulin-4 mutantpatients and mice show greatly reduced amounts of elastic fibers, adecrease in elastin-specific desmosine crosslinks and disorganization ofthe elastic fiber ultrastructure (Hucthagowder et al., 2006; McLaughlinet al., 2006; Horiguchi et al., 2009).

In a VSMC conditional knockout of fibulin-4, the VSMC were shownto be undifferentiated, together with enhanced angiotensin production,increased ERK signaling and cell proliferation (Huang et al., 2010, 2013).Aortic aneurysms caused by fibulin-4 deficiency can be prevented bytreatment with an angiotensin converting enzyme inhibitor (captopril)or an angiotensin II type 1 receptor inhibitor (losartan) (Moller et al.,2005; Huang et al., 2013), indicating a role for fibulin-4 in the regulationof angiotensin signaling andVSMChomeostasis and identifying a poten-tial approach for the treatment of patients with fibulin-4mutations.

Mutations in LTBP4 cause ARCL1C, also known as Urban–Rifkin–Davis syndrome, characterized by severe developmental emphysema,severe diverticulosis, tortuosity, enlargement and stenosis of the gastro-intestinal tract, diverticulosis of the bladder and diaphragmatic andinguinal hernias (Urban et al., 2009; Callewaert et al., 2013). Respiratoryfailure and, less frequently, intestinal perforation are causes of prema-ture death. LTBP4 utilizes 3 alternative promoters producing one small(LTBP4S) and 2 large (LTBP4L) isoforms. Human mutations identified



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Table 2 t2:1

t2:2Elastic fiber genes as targets of miR29 regulation.a

t2:3Number of binding sites (target score)

t2:4Gene miR29a-3p miR29b-3p miR29c-3p miR29b-5pt2:5ELN 3 (78) 3 (77) 3 (78) 0t2:6FBN1 2 (86) 2 (85) 2 (85) 1 (78)t2:7LOX 3 (81) 3 (81) 3 (80) 0t2:8LTBP1 0 0 0 1 (53)

a Data based on miRDB searches (http://mirdb.org/miRDB/). t2:9


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to date affect all isoforms. A knockoutmouse has only been reported forLtbp4S (Sterner-Kock et al., 2002), which nevertheless replicates theelastic fiber phenotypes seen in humans, such as developmental em-physema and the abnormal morphology of elastic fibers with largeelastin deposits with a smooth surface devoid of microfibrils (Dabovicet al., 2009; Urban et al., 2009). However, the structural anomalies ofthe gastrointestinal and urinary systems observed in humans withLTBP4 mutations are not present in Ltbp4S−/− mice, suggesting thatnormal development of the digestive system and bladder primarilyrequires LTBP4L.

An increasing body of evidence shows that LTBP4 has at least twofunctions, one related to TGFβ sequestration, and the other for facilitatingelastic fiber assembly. Indeed, the developmental emphysema observedin Ltbp4S−/− mice could be partially reversed by reducing the TGFβ2dose, but the elastic fiber abnormality was not corrected (Dabovicet al., 2009). LTBP4 isoforms are functionally specialized, with LTBP4Lpreferentially binding TGFβ, and LTBP4S associated with the ECM(Kantola et al., 2010). Consistent with phenotypic similarities betweenARCL1A and ARCL1C and between Fbln5−/− and Ltbp4S−/− mice,LTBP4 binds fibulin-5 (Noda et al., 2013) and fibrillin-1 (Isogai et al.,2003), facilitating the incorporation of fibulin-5/elastin complexes ontomicrofibrils. LTBP4 is also known to interact with fibronectin andHSPGs and is capable of supporting cell adhesion (Kantola et al., 2008).Although the importance of these functions for elastic fiber formationor TGFβ signaling remains unclear, a human mutation eliminating theC-terminal cell-attachment region results in microfibrillar bundles ofabnormally thick and wavy morphology (Callewaert et al., 2013)suggesting that a balanced binding of cells and ECMmolecules is neces-sary for LTBP4 to contribute to normal deposition of elastic fibers.

3. CL and TGFb signaling

TGFβs are a family of cytokines involved in reciprocal interactionswith the ECM. They are secreted in a latent form strongly butnon-covalently bound to their propeptides, also known as latency-associated peptides, which in turn interact with latent TGFβ-bindingproteins (LTBPs). LTBPs target latent TGFβs to the ECM by binding tofibrillin-1, fibronectin and HSPGs. Activation of latent TGFβs can occurby integrin-mediated force generation, proteolytic degradation,exposure to ROS or interaction with matricellular proteins, such asthrombospondin-1 (Horiguchi et al., 2012).

TGFβs, in turn, up-regulate the expression of many genes necessaryfor the production of elastic fibers including fibronectin (Ignotz et al.,1987), LTBPs (Ahmed et al., 1998; Weikkolainen et al., 2003), ELN(Kahari et al., 1992; Kucich et al., 1997), LOXs (Boak et al., 1994; Kimet al., 2008) and FBLN5 (Kuang et al., 2006). This regulation occurs atthe transcriptional (Ignotz et al., 1987; Ahmed et al., 1998; Kuanget al., 2006; Kim et al., 2008) or posttranscriptional level depending onthe gene (Kahari et al., 1992; Kucich et al., 1997). Posttranscriptionalregulation of ELN and fibrillin-1 (FBN1) is likely achieved in part byTGFβ-mediated suppression of the miR29 family of micro-RNAs (vanRooij et al., 2008), which have binding sites in several mRNAs encodingelastic fiber proteins (Table 2).

During the course of normal development or injury, sequestration ofTGFβ by elastic fibers serves as a negative feedback signal indicatingthat sufficient amounts and quality of ECM has been produced. Consis-tently, loss of function mutations in genes responsible for TGFβ seques-tration, including FBN1 and LTBP4, result in elevated TGFβ signaling(Neptune et al., 2003; Dabovic et al., 2009; Urban et al., 2009). However,recent studies have shown elevated TGFβ in several types of CL causedby mutations in genes not directly involved in TGFβ sequestration, butrather required for the biogenesis of elastic fibers including ELN (Huet al., 2010; Callewaert et al., 2011), fibulin-4 (Hanada et al., 2007;Renard et al., 2010) and ATP6V0A2 (Fischer et al., 2012). Thus, impairedelastic fiber function sensed by cells, in turn up-regulates TGFβ activity.Sensing of ECM dysfunction may involve integrin-mediated activation


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of TGFβ itself, which is dependent on the mechanical properties of theECM, as well as on force generation by the cells (Hinz, 2009). Consis-tently, mutations in actin (ACTA2) and myosin (MYH11) genes,required for the contractility of VSMC, are mutated in familial thoracicaortic aneurysms and are associated with increased TGFβ signaling(Renard et al., 2013).

4. The CL proteins and TGFβ in Evolution

In humans, there are three fibrillins and four LTBPs. These proteinscontainmultiple TGFβ-binding (TB) domains interspersed with numer-ous calcium-binding epidermal growth factor domains. The TB domain,which is found in noother proteins, emerged over 600 million years agoin the Eumetazoa (Peterson and Butterfield, 2005) within a singlefibrillin gene (Piha-Gossack et al., 2012). Diversification of the TB do-main led to the emergence of the first LTBP-like protein in sea urchins(Robertson et al., 2011). TGFβ also appeared at this time suggestingco-evolution of their functions (Robertson et al., 2011). Elastin appearedlater still, with the divergence of jawless fish (agnatha) and jawedvertebrates, known as gnathostomes within the phylum Chordata(Keeley, 2013). This time period coincided with a duplication eventleading to two fibrillins (Piha-Gossack et al., 2012), and the appearanceof a closed circulatory system (Faury, 2001). The single fibrillin had alsoacquired a unique hybrid domain and RGD-integrin binding sites in twoof the TB domains by this time (Piha-Gossack et al., 2012). Like fibrillin,fibulin-like proteins also existed in the Eumetazoa, much earlier thanthe emergence of elastin supporting a functional role for fibulins inde-pendent of elastic fiber assembly (Segade, 2010). Interestingly, diversi-fication of the fibulins also occurred at the same time as the evolution ofelastin. The appearance of specialized domains and the occurrence ofduplication events around the time of the evolution of elastin under-scores the potential functional significance of these specialized regionsand duplicated proteins in elastic fiber assembly.

5. CL and the secretory pathway

Several CL-related genes are required for intracellular protein traf-ficking, highlighting the importance of the secretory pathway in elasticfiber biogenesis. Loss of function mutations in ATP7A, a copper trans-porter localized to the Golgi apparatus, cause Menkes disease or amilder disease, occipital horn syndrome (OHS) (Das et al., 1995). OHS,also known as X-linked CL displays LOX deficiency associated with im-paired crosslinking of elastin and collagen (Byers et al., 1980). Recessivemutations in the gene for the A2 subunit of the vacuolar proton pump,ATP6V0A2, cause ARCL2A (Kornak et al., 2008). ATP6V0A2-deficientcells show accumulation of tropoelastin in the Golgi, Golgi fragmenta-tion and an accumulation of lamellar bodies, leading to impaired secre-tion of tropoelastin, but relatively preserved production of fibrillin-1and LOXs (Hucthagowder et al., 2009). Macrocephaly alopecia CLscoliosis (MACS) syndrome is caused by a recessive mutation in RIN2(Ras and Rab interactor 2) (Basel-Vanagaite et al., 2009). Subsequently,a recessive RIN2 mutation was also described in an Ehlers–Danlossyndrome-like condition (Syx et al., 2010). Tissues and cells from indi-viduals with RIN2 mutations show abnormal endoplasmic reticulum,Golgi apparatus, elastic and collagen fibers (Basel-Vanagaite et al.,2009; Syx et al., 2010). Geroderma osteodysplasticum, a disease related


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to CL, is caused by recessive mutations in the GORAB (goglin, Rab6interacting) (Hennies et al., 2008). GORAB is localized to theGolgi appa-ratus where it interacts with Rab6 G-proteins, which recruit kinesinmotor proteins required for the trafficking of secretory vesicles to theplasma membrane (Grigoriev et al., 2007).

6. CL and metabolism

Three conditions related to CL are caused by mutations in mole-cules required for cellular metabolism. ARCL2B, is caused by reces-sive mutations in gene for pyrroline-5-carboxylate reductase 1 (PYCR1)(Guernsey et al., 2009; Reversade et al., 2009), a mitochondrial enzymethat catalyzes the final step of proline biosynthesis (De Ingeniis et al.,2012). PYCR1 mutant cells do not show overt proline deficiency, but aresensitive to oxidative stress, suggesting that PYCR1 is required for themaintenance of mitochondrial antioxidant balance (Reversade et al.,2009). De Barsy syndrome, also known as ARCL3, can be caused bymutations in ALDH18A1 (Bicknell et al., 2008; Skidmore et al., 2011),the gene for another mitochondrial enzyme in the proline biosyntheticpathway,Δ1-pyrroline-5-carboxylate synthase (P5CS). InALDH18A1mu-tant cells the assembly of collagen type I and elastin into ECM fibers isdiminished (Bicknell et al., 2008; Skidmore et al., 2011). Arterial tor-tuosity syndrome (ATS), related to CL, is caused by mutations in theSLC2A10 gene (Coucke et al., 2006), which encodes the facilitativeglucose transporter family member 10 (GLUT10). Patients show disor-ganized elastic fibers in the arterial wall and elevated TGFβ signaling.Surprisingly, mice with inactivating missense mutations in Slc2a10 donot show phenotypes characteristic of ATS (Callewaert et al., 2008;Cheng et al., 2009). In contrast, slc2a10 knockdown in zebrafishproduces disorganization of the vasculature, wavy notochord andcardiac edema, as well as mitochondrial dysfunction and reducedTGFβ signaling (Willaert et al., 2012). SLC2A10 was shown to be trans-port dehydroascorbate (oxidized vitamin C) into mitochondria to limitthe production of ROS (Lee et al., 2010). Thus, together with PYCR1,SLC2A10 is also required for the maintenance of mitochondrial redoxbalance.

7. Concluding remarks

Human genetic studies on CL patients have revealed a network ofgenes required for elastic fiber assembly, TGFβ sequestration andactivation, vesicular trafficking in the Golgi apparatus and metabolicfunction of the mitochondria. The connections between secreted pro-teins (elastin, fibulin-4, fibulin-5, LTBP4) and their interactions withother elastic fiber-related proteins (fibronectin, lysyl oxidases, fibrillins,LTBPs) are well known and often involve direct binding. However, thetemporal and spatial hierarchy of these interactions has not beendefined yet. A combination of developmental and live imaging investi-gations will be necessary to have a comprehensive mechanistic viewof elastic fiber assembly. The involvement of the posttranslational andsorting mechanisms that occur in the secretory pathway will alsoneed to be investigated, as theymay define the timing, order andprecisebiochemical milieu in which the components can interact. Finally, therole of small molecule metabolites (ROS, proline) as well as signalingmolecules (angiotensin, TGFβ) in elastic fiber biogenesis and dysfunc-tion will need to be elucidated, as these molecules are more amenableto therapeutic modification than structural elastic fiber proteins.

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cutis laxa: intersection of elastic fiber biogenesis, tgfβ signaling, the secretory pathway and...

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