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

Goff, Carine Le; Morice‐Picard, Fanny; Dagoneau, Nathalie; Wang, Lauren W.; Perrot, Claire; Crow, Yanick J.; Bauer, Florence; Flori, Elisabeth; Prost-Squarcioni, Catherine; Krakow, Deborah; Ge, Gaoxiang; Greenspan, Daniel S.; Bonnet, Damien; Merrer, Martine Le; Münnich, Arnold; Apte, Suneel S.; Cormier‐Daire, Valérie

doi:10.1038/ng.199

Cited by 212 publications

(296 citation statements)

References 20 publications

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“…Because ADAMTSL-6 proteins associate with fibrillin-1 microfibrils and promote microfibril assembly in vitro and in vivo, it is tempting to speculate that mutations in the ADAMTSL-6 gene could lead to aberrant microfibril assembly in elastic and nonelastic tissues and thereby cause conditions similar to fibrillinopathies. Consistent with this possibility, mutations in the ADAMTSL2 gene have been associated with an acromelic dysplasia called geleophysic dysplasia, a rare autosomal recessive disorder characterized by short stature, brachydactyly, thick skin, and cardiac valvular anomalies (42). These clinical features are similar to those of Weill-Marchesani syndrome, which is also an acromeric dysplasia associated with mutations in fibrillin-1.…”

Section: Discussionsupporting

confidence: 60%

“…Le Goff et al (42) observed a significant increase in active TGF-␤ in the culture medium of fibroblasts derived from individuals with geleophysic dysplasia, along with an increased phosphorylation of Smad2 and its nuclear localization, indicative of increased TGF-␤ signaling events. They also showed that ADAMTSL-2 associates with LTBP-1, which performs a major role in the storage of latent TGF-␤ in the ECM and is similar to fibrillins in its domain structure (60).…”

Section: Discussionmentioning

confidence: 99%

“…Various ADAMTSL and ADAMTS proteins have been shown to associate with ECM molecules through their TSR domains after secretion (35, 37, 39 -44). ADAMTS-1 and -4 are capable of binding to sulfated glycosaminoglycan chains via the first TSR (39,44), and ADAMTSL-2 was recently shown to bind to LTBP-1 (42). Although the physiological functions of ADAMTSL proteins remain only poorly defined, mutations in ADAMTSL2 have been found in patients of geleophysic dysplasia, an autosomal recessive disorder characterized by short stature, brachydactyly, thick skin, and cardiac valvular anomalies (42).…”

mentioning

confidence: 99%

“…ADAMTS-1 and -4 are capable of binding to sulfated glycosaminoglycan chains via the first TSR (39,44), and ADAMTSL-2 was recently shown to bind to LTBP-1 (42). Although the physiological functions of ADAMTSL proteins remain only poorly defined, mutations in ADAMTSL2 have been found in patients of geleophysic dysplasia, an autosomal recessive disorder characterized by short stature, brachydactyly, thick skin, and cardiac valvular anomalies (42). Mutations in ADAMTSL4 have been associated with ectopia lentis, a rare autosomal-recessive disorder characterized by subluxation of the lens resulting from the disruption of the zonular fibers (45).…”

mentioning

confidence: 99%

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ADAMTSL-6 Is a Novel Extracellular Matrix Protein That Binds to Fibrillin-1 and Promotes Fibrillin-1 Fibril Formation

Tsutsui

Manabe

Yamada

et al. 2010

Journal of Biological Chemistry

122

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ADAMTS (A disintegrin and metalloproteinase with thrombospondin motifs)-like (ADAMTSL) proteins, a subgroup of the ADAMTS superfamily, share several domains with ADAMTS proteinases, including thrombospondin type I repeats, a cysteine-rich domain, and an ADAMTS spacer, but lack a catalytic domain. We identified two new members of ADAMTSL proteins, ADAMTSL-6␣ and -6␤, that differ in their N-terminal amino acid sequences but have common C-terminal regions. When transfected into MG63 osteosarcoma cells, both isoforms were secreted and deposited into pericellular matrices, although ADAMTSL-6␣, in contrast to -6␤, was barely detectable in the conditioned medium. Immunolabeling at the light and electron microscopic levels showed their close association with fibrillin-1-rich microfibrils in elastic connective tissues. Surface plasmon resonance analyses demonstrated that ADAMTSL-6␤ binds to the N-terminal half of fibrillin-1 with a dissociation constant of ϳ80 nM. When MG63 cells were transfected or exogenously supplemented with ADAMTSL-6, fibrillin-1 matrix assembly was promoted in the early but not the late stage of the assembly process. Furthermore, ADAMTSL-6 transgenic mice exhibited excessive fibrillin-1 fibril formation in tissues where ADAMTSL-6 was overexpressed. All together, these results indicated that ADAMTSL-6 is a novel microfibril-associated protein that binds directly to fibrillin-1 and promotes fibrillin-1 matrix assembly.

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Section: Discussionsupporting

confidence: 60%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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ADAMTSL-6 Is a Novel Extracellular Matrix Protein That Binds to Fibrillin-1 and Promotes Fibrillin-1 Fibril Formation

Tsutsui

Manabe

Yamada

et al. 2010

Journal of Biological Chemistry

122

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“…(11). Multiple lines of in vivo evidence have shown that dysregulated TGF-β expression, secretion, or activation from latency leads to defective bone remodeling (6,7,14). However, to date, to what extent bone homeostasis is modulated at the level of TGF-β maturation in the cell has not been fully defined.…”

mentioning

confidence: 99%

E-selectin ligand 1 regulates bone remodeling by limiting bioactive TGF-β in the bone microenvironment

Yang

Grafe

Bae

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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TGF-β is abundantly produced in the skeletal system and plays a crucial role in skeletal homeostasis. E-selectin ligand-1 (ESL-1), a Golgi apparatus-localized protein, acts as a negative regulator of TGF-β bioavailability by attenuating maturation of pro-TGF-β during cartilage homeostasis. However, whether regulation of intracellular TGF-β maturation by ESL-1 is also crucial during bone homeostasis has not been well defined. Here, we show that Esl-1 −/− mice exhibit a severe osteopenia with elevated bone resorption and decreased bone mineralization. In primary culture, Esl-1 −/− osteoclast progenitors show no difference in osteoclastogenesis. However, Esl-1 −/− osteoblasts show delayed differentiation and mineralization and stimulate osteoclastogenesis more potently in the osteoblast-osteoclast coculture, suggesting that ESL-1 primarily acts in osteoblasts to regulate bone homeostasis. In addition, Esl-1 −/− calvaria exhibit an elevated mature TGF-β/pro-TGF-β ratio, with increased expression of TGF-β downstream targets (plasminogen activator inhibitor-1, parathyroid hormone-related peptide, connective tissue growth factor, and matrix metallopeptidase 13, etc.) and a key regulator of osteoclastogenesis (receptor activator of nuclear factor κB ligand). Moreover, in vivo treatment with 1D11, a pan-TGF-β antibody, significantly improved the low bone mass of Esl-1 −/− mice, suggesting that elevated TGF-β signaling is the major cause of osteopenia in Esl-1 −/− mice. In summary, our study identifies ESL-1 as an important regulator of bone remodeling and demonstrates that the modulation of TGF-β maturation is pivotal in the maintenance of a homeostatic bone microenvironment and for proper osteoblast-osteoclast coupling.1D11 antibody | osteoblast mineralization | osteoporosis

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Molecular Genetics of M yhre Syndrome

Michot

Goff

Cormier‐Daire

2016

Encyclopedia of Life Sciences

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Myhre syndrome (MIM 139210) is a rare autosomal‐dominant disorder characterised by short stature, brachydactyly, facial dysmorphism (short palpebral fissures, prognathism and short philtrum), developmental delay with mental retardation or/and behavioural troubles, progressive deafness of mixed conductive and sensory type and a trio of thickened skin, generalised muscle hypertrophy and restricted joint mobility. Life‐threatening complications (obesity, arterial hypertension and bronchopulmonary insufficiency) are observed in the course of the disease leading to an early death. In 2011, SMAD4 (SMAD family member 4) has been identified as the disease‐causing gene. All mutations identified so far are de novo heterozygous missense mutations, mainly involving Ile500. While SMAD4 inactivation is reported in juvenile polyposis syndrome with increased colorectal cancer risk, no increased tumoural risk has been observed in Myhre syndrome. SMAD4 is a key mediator of TGF‐β (transforming growth factor beta)/BMP (bone morphogenetic protein) signalling and the understanding of the consequences of SMAD4 mutations during development will decipher new regulatory network related to TGF‐β/BMP signalling. Key Concepts Myhre syndrome is a rare genetic condition of autosomal‐dominant inheritance due to SMAD4 mutations affecting Arg496 or Ile500 residues. Myhre syndrome is characterised by short stature, brachydactyly, facial dysmorphism, developmental delay, progressive deafness and a trio of thickened skin, generalised muscle hypertrophy and restricted joint mobility. Myhre syndrome is associated to a risk of early death due to possibly life‐threatening health conditions (obesity, arterial hypertension, bronchopulmonary insufficiency, laryngotracheal stenosis and pericarditis). Similar to mothers against decapentaplegic family member 4 ( SMAD4 ) encodes the common partner SMAD of the eight‐member family of SMAD proteins. SMAD4 aggregates into heterotrimer with the receptor‐regulated SMADs (R‐SMADs) once they are activated by phosphorylation by transmembrane serine–threonine receptor kinases in response to stimulation of TGF‐β, activin or BMP receptor pathways. The SMAD4 mutations identified in Myhre syndrome are expected to disturb the monoubiquitination of SMAD4 which occurs at Lys519 and also to disturb the function of the SMAD heterotrimer which regulates the expression of target genes. Germline heterozygous mutations in SMAD4 are known to cause juvenile polyposis syndrome (JPS) and JPS‐hereditary hemorrhagic telangiectasia. The SMAD4 mutations observed in JPS and JPS‐HHT include nonsense, missense, splice‐site changes and deletions, consistent with a loss‐of‐function mechanism. Increased tumoural risk has not been observed so far in Myhre syndrome. The development of tissue‐specific mouse models of Smad4 deficiency further highlighted the important role of Smad4 in a wide range of embryonic developmental processes.

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

Cited by 212 publications

References 20 publications

ADAMTSL-6 Is a Novel Extracellular Matrix Protein That Binds to Fibrillin-1 and Promotes Fibrillin-1 Fibril Formation

ADAMTSL-6 Is a Novel Extracellular Matrix Protein That Binds to Fibrillin-1 and Promotes Fibrillin-1 Fibril Formation

E-selectin ligand 1 regulates bone remodeling by limiting bioactive TGF-β in the bone microenvironment

Molecular Genetics of M yhre Syndrome

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