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: 29.65). 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.

Download full-text


Available from: Daniel S Greenspan, Aug 18, 2015
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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 · 3.65 Impact Factor
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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 · 3.64 Impact Factor
  • Source
    • "The ADAMTS family proteins are important in connective tissue organisation, anti-angiogenesis and cell migration and attachment. Mutations in ADAMTS proteins have been associated with syndromes including Ehlers-Danlos type VIIC(Colige, et al., 2004), Weill-Marchesani syndrome(Dagoneau, et al., 2004; Kutz, et al., 2008; Morales, et al., 2009) and geleophysic dysplasia(Le Goff, et al., 2008). It is important to differentiate between patients affected by EL associated with FBN1 mutations and those with isolated EL caused by homozygous mutations in ADAMTSL4, for genetic counselling and prenatal diagnostic screening purposes. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Ectopia lentis (EL) is genetically heterogeneous with both autosomal-dominant and -recessive forms. The dominant disorder can be caused by mutations in FBN1, at the milder end of the type-1 fibrillinopathies spectrum. Recently in a consanguineous Jordanian family, recessive EL was mapped to locus 1q21 containing the ADAMTSL4 gene and a nonsense mutation was found in exon 11 (c.1785T>G, p.Y595X). In this study, 36 consecutive probands with EL who did not fulfill the Ghent criteria for MFS were screened for mutations in FBN1 and ADAMTSL4. Causative FBN1 mutations were identified in 23/36 (64%) of probands while homozygous or compound heterozygous ADAMTSL4 mutations were identified in 6/12 (50%) of the remaining probands. Where available, familial screening of these families confirmed the mutation co-segregated with the EL phenotype. This study confirms that homozygous mutations in ADAMTSL4 are associated with autosomal-recessive EL in British families. Furthermore; the first compound heterozygous mutation is described resulting in a PTC and a missense mutation in the PLAC (protease and lacunin) domain. The identification of a causative mutation in ADAMTSL4 may allow the exclusion of Marfan syndrome in these families and guide the clinical management, of particular relevance in young children affected by EL.
    Human Mutation 08/2010; 31(8):E1622-31. DOI:10.1002/humu.21305 · 5.05 Impact Factor
Show more