Three cases of Japanese acromicric/geleophysic dysplasia with FBN1 mutations: a comparison of clinical and radiological features

2017 ◽  
Vol 30 (1) ◽  
Author(s):  
Kosei Hasegawa ◽  
Chikahiko Numakura ◽  
Hiroyuki Tanaka ◽  
Mahoko Furujo ◽  
Toshihide Kubo ◽  
...  
Keyword(s):  
Growth Factor ◽  
Respiratory Distress ◽  
Transforming Growth Factor ◽  
Radiological Findings ◽  
Skeletal Dysplasias ◽  
Radiological Features ◽  
Fibrillin 1 ◽  
Hands And Feet ◽  
Tubular Bones ◽  
Acromicric Dysplasia

AbstractAcromicric dysplasia (AD) and geleophysic dysplasia (GD) are rare skeletal dysplasias characterized by short stature, acromelia, joint contracture, hepatomegaly, hoarseness and respiratory distress. Compared with GD, AD presents with milder clinical and radiological features. Radiological findings of AD and GD consist of shortened tubular bones of the hands and feet, and deformed capital femoral epiphyses. The genetic cause of AD and some cases of GD was shown to be mutations in the transforming growth factor (TGF) β-binding protein-like domain 5 of the fibrillin 1 gene (

scholarly journals Induction and Coexpression of Latent Transforming Growth Factor β-Binding Protein-1 and Fibrillin-1 in Experimental Glomerulonephritis

2005 ◽  
Vol 102 (3-4) ◽  
pp. e99-e104 ◽  
Author(s):  
Markus Porst ◽  
Christoph Daniel ◽  
Christian Plank ◽  
Harald O. Schocklmann ◽  
Dieter P. Reinhardt ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Binding Protein ◽  
Transforming Growth Factor Β ◽  
Experimental Glomerulonephritis ◽  
Fibrillin 1

scholarly journals Bovine latent transforming growth factor beta 1-binding protein 2: molecular cloning, identification of tissue isoforms, and immunolocalization to elastin-associated microfibrils.

1995 ◽  
Vol 15 (12) ◽  
pp. 6932-6942 ◽  
Author(s):  
M A Gibson ◽  
G Hatzinikolas ◽  
E C Davis ◽  
E Baker ◽  
G R Sutherland ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Binding Protein ◽  
Elastic Tissue ◽  
Tgf Beta ◽  
Fibrillin 1 ◽  
Growth Factor Beta ◽  
Nuchal Ligament ◽  
Cysteine Motifs

Monoclonal antibodies to fibrillin 1 (MP340), a component of elastin-associated microfibrils, were used to screen cDNA libraries made from bovine nuchal ligament mRNA. One of the selected clones (cL9; 1.2 kb) hybridized on Northern (RNA) blotting with nuchal ligament mRNA to two abundant mRNAs of 9.0 and 7.5 kb, which were clearly distinct from fibrillin mRNA (10 kb). Further library screening and later reverse transcription PCR by the rapid amplification of cDNA ends (RACE) technique resulted in the isolation of additional overlapping cDNAs corresponding to about 6.7 kb of the mRNA. The encoded protein exhibited sequence similarity of around 80% with a recently identified human protein named latent transforming growth factor beta 1 (TGF-beta 1)-binding protein 2 (LTBP-2), indicating that the new protein was bovine LTBP-2. This was confirmed by the specific localization of bovine LTBP-2 cDNA probes to human chromosome 14q24.3, which is the locus of the human LTBP-2 gene. The domain structure of bovine LTBP-2 is very similar to that of the human LTBP-2, containing 20 examples of 6-cysteine epidermal growth factor-like repeats, 16 of which have the consensus sequence for calcium binding, together with 4 examples of 8-cysteine motifs characteristic of fibrillins and LTBP-1. A 4-cysteine sequence which is unique to bovine LTBP-2 and which has similarity to the 8-cysteine motifs was also present. Antibodies raised to two unique bovine LTBP-2 peptides specifically localized in tissue sections to the elastin-associated microfibrils, indicating that LTBP-2 is closely associated with these structures. Immunoblotting experiments identified putative LTBP-2 isoforms as a 260-kDa species released into the medium by cultured elastic tissue cells and as larger 290- and 310-kDa species in tissue extracts. A major proportion of tissue-derived LTBP-2 required treatment with 6 M guanidine for solubilization, indicating that the protein was strongly bound to the microfibrils. Most of the guanidine-solubilized LTBP-2 appeared to be monomeric, indicating that it was not involved in disulfide-bonded aggregation either with itself or with latent TGF-beta. Additional LTBP-2 was resistant to solubilization with 6 M guanidine but was readily extracted with a reductive saline solution. This treatment is relatively specific for solubilization of microfibrillar constituents including fibrillin 1 and microfibril-associated glycoprotein. Therefore, it can be inferred that some LTBP-2 is bound covalently to the microfibrils by reducible disulfide linkages. The evidence suggests that LTBP-2 has a direct role in elastic fiber structure and assembly which may be independent of its growth factor-binding properties. Thus, LTBP-2 appears to share functional characteristics with both LTBP-1 and fibrillins.

scholarly journals O-Fucosylation of ADAMTSL2 is required for secretion and is impacted by geleophysic dysplasia-causing mutations

2020 ◽  
Vol 295 (46) ◽  
pp. 15742-15753
Author(s):  
Ao Zhang ◽  
Steven J. Berardinelli ◽  
Christina Leonhard-Melief ◽  
Deepika Vasudevan ◽  
Ta-Wei Liu ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Consensus Sequence ◽  
Transforming Growth Factor Β ◽  
Connective Tissue Disorder ◽  
Matricellular Protein ◽  
Consensus Sequences ◽  
Skeletal Defects ◽  
Fibrillin 1 ◽  
Small Hands ◽  
Hands And Feet

ADAMTSL2 mutations cause an autosomal recessive connective tissue disorder, geleophysic dysplasia 1 (GPHYSD1), which is characterized by short stature, small hands and feet, and cardiac defects. ADAMTSL2 is a matricellular protein previously shown to interact with latent transforming growth factor-β binding protein 1 and influence assembly of fibrillin 1 microfibrils. ADAMTSL2 contains seven thrombospondin type-1 repeats (TSRs), six of which contain the consensus sequence for O-fucosylation by protein O-fucosyltransferase 2 (POFUT2). O-fucose–modified TSRs are subsequently elongated to a glucose β1-3-fucose (GlcFuc) disaccharide by β1,3-glucosyltransferase (B3GLCT). B3GLCT mutations cause Peters Plus Syndrome (PTRPLS), which is characterized by skeletal defects similar to GPHYSD1. Several ADAMTSL2 TSRs also have consensus sequences for C-mannosylation. Six reported GPHYSD1 mutations occur within the TSRs and two lie near O-fucosylation sites. To investigate the effects of TSR glycosylation on ADAMTSL2 function, we used MS to identify glycan modifications at predicted consensus sequences on mouse ADAMTSL2. We found that most TSRs were modified with the GlcFuc disaccharide at high stoichiometry at O-fucosylation sites and variable mannose stoichiometry at C-mannosylation sites. Loss of ADAMTSL2 secretion in POFUT2−/− but not in B3GLCT−/− cells suggested that impaired ADAMTSL2 secretion is not responsible for skeletal defects in PTRPLS patients. In contrast, secretion was significantly reduced for ADAMTSL2 carrying GPHYSD1 mutations (S641L in TSR3 and G817R in TSR6), and S641L eliminated O-fucosylation of TSR3. These results provide evidence that abnormalities in GPHYSD1 patients with this mutation are caused by loss of O-fucosylation on TSR3 and impaired ADAMTSL2 secretion.

scholarly journals The Effects of Dasatinib in Experimental Acute Respiratory Distress Syndrome Depend on Dose and Etiology

2015 ◽  
Vol 36 (4) ◽  
pp. 1644-1658 ◽  
Author(s):  
Gisele P. Oliveira ◽  
Johnatas D. Silva ◽  
Patricia S. Marques ◽  
Cassiano F. Gonçalves-de-Albuquerque ◽  
Heloísa L. Santos ◽  
...  
Keyword(s):  
Acute Respiratory Distress Syndrome ◽  
Growth Factor ◽  
Tyrosine Kinase ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Distress Syndrome ◽  
Transforming Growth Factor ◽  
Diffuse Alveolar Damage ◽  
Lung Mechanics ◽  
Dose Monitoring

Background/Aims: Evidence suggests that tyrosine-kinase inhibitors may attenuate lung inflammation and fibrosis in experimental acute respiratory distress syndrome (ARDS). We hypothesized that dasatinib, a tyrosine-kinase inhibitor, might act differently depending on the ARDS etiology and the dose. Methods: C57/BL6 mice were divided to be pre-treated with dasatinib (1mg/kg or 10mg/kg) or vehicle (1% dimethyl-sulfoxide) by oral gavage. Thirty-minutes after pre-treatment, mice were subdivided into control (C) or ARDS groups. ARDS animals received Escherichia coli lipopolysaccharide intratracheally (ARDSp) or intraperitoneally (ARDSexp). A new dose of dasatinib or vehicle was administered at 6 and 24h. Results: Forty-eight hours after ARDS induction, dasatinib 1mg/kg yielded: improved lung morphofunction and reduced cells expressing toll-like receptor (TLR)-4 in lung, independent of ARDS etiology; reduced neutrophil and levels of interleukin (IL)-6, IL-10 and transforming growth factor (TGF)-β in ARDSp. The higher dose of dasatinib caused no changes in lung mechanics, diffuse alveolar damage, neutrophil, or cells expressing TLR4, but increased IL-6, vascular endothelial growth factor (VEGF), and cells expressing Fas receptor in lung in ARDSp. In ARDSexp, it improved lung morphofunction, increased VEGF, and reduced cells expressing TLR4. Conclusion: Dasatinib may have therapeutic potential in ARDS independent of etiology, but careful dose monitoring is required.

scholarly journals Transforming growth factor ? induces fibroblast fibrillin-1 matrix formation

2002 ◽  
Vol 46 (11) ◽  
pp. 3000-3009 ◽  
Author(s):  
Eugene Y. Kissin ◽  
Raphael Lemaire ◽  
Joseph H. Korn ◽  
Robert Lafyatis
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Fibrillin 1

scholarly journals Clinical and genetic characteristics of rare variants of acromelic skeletal dysplasias caused by mutations in the FBN1 gene

2021 ◽  
Vol 9 (3) ◽  
pp. 327-337
Author(s):  
Tatyana V. Markova ◽  
Vladimir M. Kenis ◽  
Evgenii V. Melchenko ◽  
Tatyana S. Nagornova ◽  
Aysylu F. Murtazina ◽  
...  
Keyword(s):  
Amino Acid ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Polypeptide Chain ◽  
Clinical Manifestations ◽  
Genetic Characteristics ◽  
Fbn1 Gene ◽  
Growth Factor Beta ◽  
Acromicric Dysplasia

BACKGROUND: Geleophysic dysplasia and acromicric dysplasia are rare hereditary diseases characterized by dwarfism and dysplastic skeletal features. In the literature, only a few cases of geleophysic dysplasia and acromicric dysplasia caused by mutations in the FBN1 gene are described. CLINICAL CASES: A description of the clinical and genetic characteristics of three female patients with acromelic dysplasias caused by three types of missense mutations in the FBN1 gene is presented. In two patients, on the basis of clinical manifestations and radiographic examination, acromicric dysplasia, and in one patient geleophysic dysplasia were diagnosed. It was shown that all identified mutations were localized in exons of the FBN1 gene encoding the amino acid sequence of the fifth domain, which has homology with transforming growth factor-beta. DISCUSSION: We have analyzed the clinical and genetic correlations to confirm the previously stated hypothesis about the occurrence of a severe phenotype of geleophysic dysplasia in patients with the c.5206T C mutation. This mutation is characterized by the replacement of cysteine by arginine in the position of the polypeptide chain leading to moderate clinical manifestations of acromicric dysplasia in patients with the c.5284 G A (p. Gly1762Ser). It was shown that the previously undescribed substitution c.5177G A (p.Gly1726Asp and another previously described mutation in this codon resulted in the replacement of glutamine with valine. This mutation causes the appearance of a less pronounced phenotype of AD. CONCLUSIONS: Based on the results of the examination of three Russian patients and analysis of clinical and radiographic parameters described in the literature, we reported that mutations in the FBN1 gene disrupted the amino acid sequence of the fifth like transforming growth factor-beta domain of fibrillin type 1. Importantly, these mutations are responsible for the occurrence of geleophysic dysplasia and acromicric dysplasia. However, the most severe clinical manifestations were observed in patients with mutations leading to the substitution of cysteine for arginine at the position of the polypeptide chain 1736. This may lead to affecting the transforming growth factor-beta signaling pathway.

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