ADAMTSL2 mutations in geleophysic dysplasia demonstrate a role for ADAMTS-like proteins in TGF-β bioavailability regulation

Département de Génétique, Unité INSERM U781, Université Paris Descartes, Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades, 75015 Paris, France.
Nature Genetics (Impact Factor: 29.35). 09/2008; 40(9):1119-23. DOI: 10.1038/ng.199
Source: PubMed

ABSTRACT Geleophysic dysplasia is an autosomal recessive disorder characterized by short stature, brachydactyly, thick skin and cardiac valvular anomalies often responsible for an early death. Studying six geleophysic dysplasia families, we first mapped the underlying gene to chromosome 9q34.2 and identified five distinct nonsense and missense mutations in ADAMTSL2 (a disintegrin and metalloproteinase with thrombospondin repeats-like 2), which encodes a secreted glycoprotein of unknown function. Functional studies in HEK293 cells showed that ADAMTSL2 mutations lead to reduced secretion of the mutated proteins, possibly owing to the misfolding of ADAMTSL2. A yeast two-hybrid screen showed that ADAMTSL2 interacts with latent TGF-beta-binding protein 1. In addition, we observed a significant increase in total and active TGF-beta in the culture medium as well as nuclear localization of phosphorylated SMAD2 in fibroblasts from individuals with geleophysic dysplasia. These data suggest that ADAMTSL2 mutations may lead to a dysregulation of TGF-beta signaling and may be the underlying mechanism of geleophysic dysplasia.

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Available from: Daniel S Greenspan, Sep 26, 2015
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    • "Potential evidence for ADAMTS involvement in TGF signaling came from analysis of fibroblasts isolated from patients with geleophysic dysplasia caused by ADAMTSL2 mutations, which secreted more latent and active TGF and showed evidence of enhanced TGF signaling [69]. In addition, recombinant ADAMTSL2 protein interacts directly with FBN1, FBN2, and LTBP1 [19] [69] [75]. Although it is not known if these proteins form a tri-molecular complex or compete with each other in the binding, ADAMTSL2 seems to sit squarely within a context relevant to TGF regulation. "
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    ABSTRACT: The ADAMTS (a disintegrin-like and metalloproteinase domain with thrombospondin-type 1 motifs) protein superfamily includes 19 secreted metalloproteases and 7 secreted ADAMTS-like (ADAMTSL) glycoproteins. The possibility of functional linkage between ADAMTS proteins and fibrillin microfibrils was first revealed by a human genetic consilience, in which mutations in ADAMTS10 and ADAMTS17 and ADAMTSL2 and ADAMTSL4 were found to phenocopy rare genetic disorders caused by mutations in fibrillin-1 (FBN1), the major microfibril component in adults. The manifestations of these ADAMTS gene disorders in humans and animals suggested that ADAMTS proteins participated in the structural and regulatory roles of microfibrils. Whereas two such disorders, Weill-Marchesani syndrome 1 and Weill-Marchesani-like syndrome involve proteases (ADAMTS10 and ADAMTS17, respectively), geleophysic dysplasia and isolated ectopia lentis in humans involve ADAMTSL2 and ADAMTSL4, respectively, which are not proteases. In addition to broadly similar dysmorphology, individuals affected by Weill-Marchesani syndrome 1, Weill-Marchesani-like syndrome or geleophysic dysplasia each show characteristic anomalies suggesting molecule-, tissue-, or context-specific functions for the respective ADAMTS proteins. Ectopia lentis occurs in each of these conditions except geleophysic dysplasia, and is due to a defect in the ciliary zonule, which is predominantly composed of FBN1 microfibrils. Together, this strongly suggests that ADAMTS proteins are involved either in microfibril assembly, stability, and anchorage, or the formation of function-specific supramolecular networks having microfibrils as their foundation. Here, the genetics and molecular biology of this subset of ADAMTS proteins is discussed from the perspective of how they might contribute to fully functional or function-specific microfibrils. Copyright © 2015. Published by Elsevier B.V.
    Matrix biology: journal of the International Society for Matrix Biology 05/2015; 326. DOI:10.1016/j.matbio.2015.05.004 · 5.07 Impact Factor
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    • "A mutation in ADAMTS10 is associated with Weill-Marchesani syndrome (WMS), a disorder that is characterized by the short body size, short fingers and toes, joint stiffness and eye anomalies (Dagoneau et al., 2004). In addition, a mutation in ADAMTSL2 (ADAMTS-like2) leads to geleophysic dysplasia, a condition characterized by short stature and digit abnormalities (Le Goff et al., 2008). Finally, gene variants in human ADAMTS10, ADAMTS17 and ADAMTSL3 (ADAMTS-like3) are associated with variation in human height (Gudbjartsson et al., 2008; Lettre et al., 2008; Weedon et al., 2008). "
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    ABSTRACT: Organismal growth and body size are influenced by both genetic and environmental factors. We have utilized the strong molecular genetic techniques available in the nematode Caenorhabditis elegans to identify genetic determinants of body size. In C. elegans, DBL-1, a member of the conserved family of secreted growth factors known as the Transforming Growth Factor β superfamily, is known to play a major role in growth control. The mechanisms by which other determinants of body size function, however, is less well understood. To identify additional genes involved in body size regulation, a genetic screen for small mutants was previously performed. One of the genes identified in that screen was sma-21. We now demonstrate that sma-21 encodes ADT-2, a member of the ADAMTS (a disintegrin and metalloprotease with thrombospondin motifs) family of secreted metalloproteases. ADAMTS proteins are believed to remodel the extracellular matrix and may modulate the activity of extracellular signals. Genetic interactions suggest that ADT-2 acts in parallel with or in multiple size regulatory pathways. We demonstrate that ADT-2 is required for normal levels of expression of a DBL-1-responsive transcriptional reporter. We further demonstrate that adt-2 regulatory sequences drive expression in glial-like and vulval cells, and that ADT-2 activity is required for normal cuticle collagen fibril organization. We therefore propose that ADT-2 regulates body size both by modulating TGFβ signaling activity and by maintaining normal cuticle structure.
    Developmental Biology 04/2011; 352(1):92-103. DOI:10.1016/j.ydbio.2011.01.016 · 3.55 Impact Factor
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    • "Another rare disorder in which skin thickening and joint contractures are characteristic features, is geleophysic dysplasia (GD), an acromelic dysplasia in which short stature, characteristic facies, a pleasant temperament, shortening of the distal phalanges, and tracheal stenosis are also present [19]. GD results from recessively inherited ADAMTSL2 mutations [20]. The medium of GD fibroblasts was found to contain high levels of TGFβ, and GD fibroblasts were shown to have evidence of enhanced TGFβ signaling [20]. "
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    ABSTRACT: Musladin-Lueke Syndrome (MLS) is a hereditary disorder affecting Beagle dogs that manifests with extensive fibrosis of the skin and joints. In this respect, it resembles human stiff skin syndrome and the Tight skin mouse, each of which is caused by gene defects affecting fibrillin-1, a major component of tissue microfibrils. The objective of this work was to determine the genetic basis of MLS and the molecular consequence of the identified mutation. We mapped the locus for MLS by genome-wide association to a 3.05 Mb haplotype on canine chromosome 9 (CFA9 (50.11-54.26; p(raw) <10(-7))), which was homozygous and identical-by-descent among all affected dogs, consistent with recessive inheritance of a founder mutation. Sequence analysis of a candidate gene at this locus, ADAMTSL2, which is responsible for the human TGFβ dysregulation syndrome, Geleophysic Dysplasia (GD), uncovered a mutation in exon 7 (c.660C>T; p.R221C) perfectly associated with MLS (p-value=10(-12)). Murine ADAMTSL2 containing the p.R221C mutation formed anomalous disulfide-bonded dimers when transiently expressed in COS-1, HEK293F and CHO cells, and was present in the medium of these cells at lower levels than wild-type ADAMTSL2 expressed in parallel. The genetic basis of MLS is a founder mutation in ADAMTSL2, previously shown to interact with latent TGF-β binding protein, which binds fibrillin-1. The molecular effect of the founder mutation on ADAMTSL2 is formation of disulfide-bonded dimers. Although caused by a distinct mutation, and having a milder phenotype than human GD, MLS nevertheless offers a new animal model for study of GD, and for prospective insights on mechanisms and pathways of skin fibrosis and joint contractures.
    PLoS ONE 09/2010; 5(9). DOI:10.1371/journal.pone.0012817 · 3.23 Impact Factor
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