Human Molecular Genetics, 2011, Vol. 20, Review Issue 2 doi:10.1093/hmg/ddr361 Advance Access published on August 31, 2011

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The ADAMTS(L) family and human genetic disorders Carine Le Goff1,∗ and Vale´rie Cormier-Daire2 1

De´partement de Ge´ne´tique, Unite´ INSERM U781, Universite´ Paris Descartes, Sorbonne Paris Cite´, Tour Lavoisier 2nd floor, 149 rue de Se`vres, Paris 75015, France and 2De´partement de Ge´ne´tique, Unite´ INSERM U781, Universite´ Paris Descartes, Sorbonne Paris Cite´, Hoˆpital Necker Enfants Malades, Paris, France Received August 3, 2011; Revised and Accepted August 11, 2011

ADAMTS designates a family of 19 secreted enzymes, whose the first member ADAMTS1 was described in 1997. The ADAMTS family has a role in extracellular matrix degradation and turn over and has previously been involved in various human biological processes, including connective tissue structure, cancer, coagulation, arthritis, angiogenesis and cell migration. More recently, the ADAMTS(L) family has been described, sharing the same ancillary domain but distinct by the absence of any enzyme activity. Mutations in ADAMTS13, ADAMTS2, ADAMTS10, ADAMTS17, ADAMTSL2 and ADAMTSL4 have been identified in distinct human genetic disorders ranging from thrombotic thrombocytopenic purpura to acromelic dysplasia. The aim of our review was to emphasize the role of this family in the extracellular matrix based on human phenotypes so far identified in relation with ADAMTS(L) mutations.

INTRODUCTION The superfamily of ADAMTS (A Disintegrin and Metalloproteinase with thrombospondin motifs) includes 19 distinct ADAMTS which are secreted enzymes and, at least, seven ADAMTS-like proteins without enzymatic activity (1 – 3). The ADAMTS have two domains: the catalytic domain at the N terminus and the ancillary domain at their C terminus which is essential for specific interaction with the substrate and are distinct from the membrane anchored ADAMs by one or more thrombospondin type I repeats. They are synthesized as inactive zymogens, and their N-terminal propeptide is cleaved by the furin, a proprotein convertase. This posttranslational modification is necessary at their activation. Matrix metalloproteases have a role in extracellular matrix degradation and turn over as well as in proteolysis of cell surface and soluble proteins (3). The ADAMTS proteases family is divided in 10 clades, defined by similar primary structure and substrate specificity. For example, ADAMTS4 and 5, which are proteoglycanases, belong to a same clade (4,5), whereas ADAMTS2, 3 and 14, which are procollagen N propeptidases, constitute another clade. The ADAMTS family has been involved in various human biological processes (normal or pathological), including connective tissue structure, cancer, coagulation, arthritis, angiogenesis and cell migration. The recent identification of

ADAMTS mutations in human disorders has also supported regulatory function in the extracellular matrix. The subfamily of ADAMTS-like proteins is homologous to the ADAMTS ancillary domains but lacks the protease domain and hence lacks catalytic activity. Like the ADAMTS, they are components of extracellular matrix. ADAMTSL1 and ADAMTSL3 proteins are closely related secreted glycoproteins, whereas ADAMTSL2 has a different domain structure (6 – 8). ADAMTSL4 and ADAMTSL6 have a similar structure and both related to fibrillin-1 (2 – 9). Their function are unknown but it has been recently shown that Papilin, a basement membrane component closely structurally related to the ADAMTSL family, can act as a non-competitive inhibitor of ADAMTS2 in vitro (10). We will review the human disorders yet identified in relation with ADAMTS(L) mutations (see Fig. 1 and Table 1) and will bring novel insight in the role of this recently described family.

RESULTS ADAMTS13 mutations and thrombotic thrombocytopenic purpura Thrombotic thrombocytopenic purpura (TTP, MIM 274150) is an autosomal recessive disorder characterized by widespread

∗

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# The Author 2011. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]

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Figure 1. Structure of ADAMTS and ADAMTS(L) yet involved in human genetic disorders.

microvascular thrombosis involving the capillaries and arterioles of the brain and other organs such as the heart, kidney, pancreas, spleen, mesentery and adrenal gland (11– 13). TTP leads to early death unless patients are treated with plasma exchange or infusion. ADAMTS13 mutations cause inherited TTP, whereas deficiency of ADAMTS13 due to autoimmune inhibitors cause acquired TTP (14). ADAMTS13 constitutes a unique clade characterized by a C-terminal structure with a CUB domain (2). In the circulation, endothelial von Willebrand factor (VWF) polymer is converted to plasma multimers by ADAMTS13. ADAMTS13 mutations lead to VWF platelet aggregation and then abnormal coagulation in targeted organs (15). ADAMTS2 mutations and Ehlers – Danlos syndrome type VIIC Ehlers – Danlos syndrome (EDS) type VIIC (MIM 225410) is a recessively inherited connective tissue disorder, characterized by extreme skin fragility, characteristic facies, joint laxity, lax skin, umbilical hernia and blue sclera (16,17). EDS type VIIC results from a defect in the processing of type I procollagen to collagen and is due to ADAMTS2 mutations (18). ADAMTS2 encodes a procollagen N-proteinase (PNP), which normally removes the aminopropeptides of type I, II. While this biosynthetic pathway is crucial in a wide number of tissues, the predominant skin involvement of EDS type VIIC is probably explained by redundant functions of ADAMTS3 and ADAMTS14, which are also PNP, in other tissues; they all have the ability to process the amino-peptide of the procollagens I, II and III in vitro. Their gene expression pattern during mouse embryogenesis has shown how closely related proteases with similar substrate may have distinct biological roles owing to tissue-specific gene expression (19). For

example, during the mouse embryogenesis, Adamts3 only is largely expressed in collagen-I-rich tissues and in cartilage, rich in collagen II. ADAMTS3 induced procollagen I processing in dermatosparactic fibroblasts confirming a potential role in procollagen I cleavage during the development. On the other hand, Adamts2 is specifically co-expressed with collagen III in the lung and aorta and Adamts22/2 mice had abnormal lungs with a decreased parenchymal density (19). ADAMTS10 mutations and Weill –Marchesani syndrome Weill –Marchesani syndrome (WMS, MIM 277600) belongs to the acromelic dysplasia group which also includes geleophysic dysplasia (GD) and acromicric dysplasia (AD). They are all characterized by short stature (, 23SD), short hands and feet, joint limitations and thick skin. WMS is distinct from GD and AD by the presence of dislocation of microspherophakic lens which may be associated with severe myopia, glaucoma or cataract (20,21). Two modes of inheritance have been reported: autosomal dominant and autosomal recessive. We first showed that Fibrillin 1 (FBN1) is responsible for the dominant form of WMS (22). In the mean time, we identified mutations in ADAMTS10 [A Disintegrin-like And Metalloproteinase domain (reprolysin type) with ThromboSpondin type 1 repeats] in the autosomal recessive form of WMS. Mutations were located in the metalloprotease domain and all predicted premature termination of translation (23). The review of 128 WMS patients reported in the literature does not allow finding any significant distinctive feature, supporting the clinical homogeneity of the disorder (24). WMS appears to be a clinically homogenous but genetically heterogeneous condition. The function of ADAMTS10 is unknown. However, the combination of its pattern of expression during development

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Table 1. ADAMTS/ADAMTS-like in human genetic disease ADAMTS

Function

Human disease

Phenotype

ADAMTS2 ADAMTS10

Procollagen N propeptidase Unknown

EDS type VIIC WMS

Fragile skin joint laxity Short stature and extremities Thick skin Joint limitation Lens dislocation

ADAMTS17

Unknown

Weill –Marchesani-like syndrome l

Short stature Lens dislocation

ADAMTS13 ADAMTSL2

VWF cleaving-protease Unknown

TTP GD

Capillaries and arterioles (heart, brain, kidney) Thrombosis of Short stature and extremities Thick skin Joint limitation Cardiac valvular disease

ADAMTSL4

Unknown

EL

Lens dislocation

with the clinical manifestations of WMS supported a specific role of ADAMTS10 in cartilage, skin and lens zonular fibres. Moreover, the involvement of ADAMTS10 and FBN1 in the same disorder was highly suggestive of a functional relationship between ADAMTS10 and fibrillin-1. Very recently, a direct interaction between ADAMTS10 and fibrillin-1 has been demonstrated with ADAMTS10 promoting FBN1 deposition in extracellular matrix of cultured fibroblasts. These novel findings support a role of ADAMTS10 in microfibril biogenesis (25). ADAMTS17 mutations and Weill –Marchesani-like syndrome Three different homozygous truncating ADAMTS17 mutations have been identified in patients presenting by a ‘Weill– Marchesani-like’ syndrome (26). Patients present with short stature and lens dislocation (MIM 613195), but have no brachydactyly, decreased joint mobility or thick skin. To date, ADAMTS17 function is unknown. However, the clinical and genetic findings support that ADAMTS10 and ADAMTS17 play a critical role in crystalline lens zonules and connective tissue formations. ADAMTS-like 2 mutations and GD GD (MIM231050) is the more severe form of the acromelic dysplasia and is transmitted with an autosomal recessive mode of inheritance (27). The main distinctive features are facial features: ‘happy’ face with full cheeks, shortened nose, hypertelorism, long flat philtrum, thin upper lip—a progressive cardiac valvular thickening often leading to an early death, toe walking, tracheal stenosis, respiratory insufficiency and lysomal-like storage vacuoles in various tissues. Radiological manifestations include delayed bone age, cone-shaped epiphyses, shortened long tubular bones and ovoid vertebral bodies. Up till now, we have identified mutations in ADAMTSL2 gene in 14 GD patients (28,29). This gene encodes a secreted glycoprotein of unknown function. The expression pattern of

Gene associated with the same phenotype FBN1

FBN1

FBN1

ADAMTSL2 during development included the heart, skin, tracheal wall, skeletal muscle, lung, hypertrophic and resting zones of the cartilage growth plate and was highly correlated with the clinical manifestations of GD (28). Functional studies in HEK293 cells showed that ADAMTSL2 mutations lead to a decreased secretion of the mutated proteins, possibly due to the misfolding of ADAMTSL2. A yeast twohybrid screen has revealed that ADAMTSL2 interacts with Latent TGFb Binding Protein 1 (LTBP1). We have finally observed a significant increase in total and active TGFb in the culture medium and the nuclear localization of phosphorylated Smad2 in GD fibroblasts. These data suggest that a dysregulation of TGFb signalling is the underlying mechanism of GD and that ADAMTSL2 is directly involved in TGFb bioavailability (28). However, the absence of ADAMTSL2 mutations in 19 of 33 GD patients suggested genetic heterogeneity (29).We therefore performed exome sequencing in two GD cases with no ADAMTSL2 mutations. Because AD has yet unknown molecular basis, we also performed exome sequencing in three AD cases. AD (MIM 102370) is transmitted with an autosomal dominant mode of inheritance and is characterized by facial features: round face, well-defined eyebrows, long eyelashes, a bulbous nose with anteverted nostrils, a long and prominent philtrum, thick lips with a small mouth—a hoarse voice, pseudomuscular build and skeleton features (internal notch of the femoral head, internal notch of the second metacarpal and the external notch of the fifth metacarpal (30,31). We searched for a shared mutated gene among the five exomes (two GD and three AD) and identified heterozygous FBN1 mutations in the two disorders. We identified a total of 16 heterozygous FBN1 mutations (15 missense and 1 insertion) all located in exons 41– 42, encoding TGFb-binding protein-like domain 5 (TB5) of FBN1 in 19 GD and 10 AD cases (32). While GD has been described as an autosomal recessive disorder, the identification of heterozygous FBN1 mutations demonstrates a dominant form of GD, strictly fulfilling the diagnostic criteria for GD (including progressive cardiac valvular thickening, and early death in 3 of 19). Similarly,

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all AD cases fulfilled the diagnostic criteria of AD and had no cardiac involvement or early death. Microfibrillar network disorganization and enhanced TGFb signalling were also consistently observed in GD/AD fibroblasts (32). Importantly, a direct interaction between ADAMTSL2 and FBN1 was demonstrated, suggesting a dysregulation of FBN1/ADAMTSL2/TGFb interrelationship as the underlying mechanism of the short stature phenotypes. ADAMTS-like 4 mutations and isolated ectopia lentis A homozygous ADAMTSL4 mutation was recently identified in autosomal recessive isolated ectopia lentis (EL; MIM 225100) (33). EL is a rare condition characterized by partial or complete displacement of the lens from its space. Patients with EL commonly present with marked loss in visual acuity that varies with the degree of lens subluxation, and various complications can be observed, including myopia, retinal detachment, cataract and glaucoma. EL is due to the disruption of the zonular fibres, which are microfibrillar structures, supporting the lens. The role of ADAMTSL4 in zonular fibres is unknown. But interestingly, LTBP2 null mutations have been identified in an autosomal recessive ocular syndrome characterized by megalocornea, spherophakia and secondary glaucoma (34). Remembering the link between ADAMTSL2 and LTBP1 and the co-localization of ADAMTSL4 and LTBP2 both in the eye, these findings also support a functional link between ADAMTSL4 and LTBP2.

ADAMTS19), ADAMTSL2/ADAMTSL4, belong to four different subclades. However, they are all related with the microfibrillar network and each of them is responsible for a phenotype which might be due also to FBN1 mutations (from isolated EL to WMS and GD); in addition, all four are characterized by a PLAC domain at their C-terminal domain supporting also a functional link (22,32,35). They illustrated the dual function of these proteins playing either a structural role or a regulatory role in the microfibrillar network. The finding of EL in association with ADAMTS10, 17, ADAMTSL4, FBN1and LTPB2 mutations support the cooperative involvement of these proteins in the microfibrillar structure of the crystalline lens zonules. The direct interaction of ADAMTS10 and ADAMTSL2 with FBN1 and LTBP1 and the finding of enhanced TFGb signalling in GD/AD due to ADAMTSL2 or FBN1 mutations also support a role of this family in microfibrillar biogenesis and in TGFb signalling. ADAMTSL6, which has not been yet associated with any human disorder, is probably another actor of this complex network, based on the recent findings of its binding to fibrillin 1 microfibrils, promoting fibrillin-1 matrix assembly (9). Ongoing studies should contribute to further understand the regulatory networks and context-dependent mechanisms involved in microfibrillar biogenesis and in TGFb signalling. Conflict of Interest statement. None declared.

FUNDING CONCLUSION Until recently, the ADAMTS(L) proteins were mainly described at the structural level. The identification of mutations in human genetic disorders has been crucial in the understanding of the role of this novel family of proteins in the extracellular matrix, both as structural components and as regulatory actors. Although ADAMTS proteases have similar primary structure, they are sub-classified in 10 different clades depending on their structural or functional characteristics. Only a few human genetic disorders have been yet identified in relation with ADAMTS(L) mutations, but the restricted number of tissues involved in these disorders highlights also their specific pattern of expression during development. ADAMTS13 or VWF protease constitutes a unique clade with a specific function, not shared by any other clade. ADAMTS2, 3 and 14 constitute another clade. They are all three procollagen N propeptidase, involved in procollagen processing with presumably redundant function. However, their individual and specific pattern of expression also suggests that they will be involved in distinct human disorders. ADAMTS2 mutations have been identified in an inherited skin disorder, EDS VIIc. ADAMTS14 is expressed in mature dermis skin. Finally, ADAMTS3 is specifically expressed in cartilage bone and musculo-tendinous structures and might be a good candidate gene for osteochondrodysplasia. The four other ADAMTS(L), namely ADAMTS10 (same clade than ADAMTS6), ADAMTS17 (same clade than

This research was supported by French National Research Agency (ANR) award R09183KS (to V.C.-D.).

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