Phenotypic correction of the defective fibronectin extracellular matrix of Ehlers-Danlos syndrome fibroblasts

1991 ◽  
Vol 15 (12) ◽  
pp. 1183-1194 ◽  
Author(s):  
S BARLATI ◽  
L MORO ◽  
R GARDELLA ◽  
M COLOMBI
Keyword(s):  
Extracellular Matrix ◽  
Ehlers Danlos Syndrome ◽  
Danlos Syndrome

scholarly journals Abnormal type III collagen produced by an exon-17-skipping mutation of the COL3A1 gene in Ehlers-Danlos syndrome type IV is not incorporated into the extracellular matrix

1995 ◽  
Vol 311 (3) ◽  
pp. 939-943 ◽  
Author(s):  
A A Chiodo ◽  
D O Sillence ◽  
W G Cole ◽  
J F Bateman
Keyword(s):  
Extracellular Matrix ◽  
Triple Helix ◽  
Type Iii Collagen ◽  
Syndrome Type ◽  
Ehlers Danlos Syndrome ◽  
Type Iii ◽  
Type Iv ◽  
Col3a1 Gene ◽  
Collagen Molecules ◽  
Danlos Syndrome

A novel heterozygous mutation of the COL3A1 gene that encodes the alpha 1(III) chains of type III collagen was identified in a family with the acrogeric form of Ehlers-Danlos syndrome type IV (EDS-IV). Cultured dermal fibroblasts produced normal and shortened alpha 1(III) chains. The triple helix of the latter chain was shortened owing to a 33 amino acid deletion of Gly-184 to Pro-216. The corresponding region of cDNA lacked 99 base pairs from nucleotides 1051 to 1149. The deletions corresponded exactly to the normal sequence encoded by exon 17 of the COL3A1 gene. The proband was heterozygous for a T to G transversion at position +2 of intron 17, which resulted in skipping of exon 17. The splicing defect was not corrected by growing the fibroblasts at 33 degrees C and no other splicing variants were identified at 33 or 37 degrees C. The affected brother had the same mutation but his unaffected mother did not. Heterotrimeric type III collagen molecules containing normal and mutant chains were retained within the cell. The mutant homotrimeric molecules were modified and secreted normally and were thermally stable. These normal characteristics of the mutant homotrimers suggested that the loss of ten Gly-Xaa-Yaa triplets (where Gly-Xaa-Yaa is a repetitive amino acid triplet structure in which Xaa and Yaa are other amino acids, proline and hydroxyproline being more common in the Yaa position) did not adversely affect the formation and stability of the triple helix or the structural requirements for secretion. However, the mutant homotrimers were not incorporated into the extracellular matrix of an in vitro model of EDS-IV dermis. The EDS-IV phenotype in this family was probably due to a deficiency in the amount of normal type III collagen available for formation of the heterotypic collagen fibrils of the extracellular matrix. Intracellular and extracellular quality-control mechanisms prevented the incorporation of heterotrimeric and homotrimeric mutant type III collagen molecules into the cross-linked extracellular matrix.

scholarly journals Transcriptome Profiling of Primary Skin Fibroblasts Reveal Distinct Molecular Features Between PLOD1- and FKBP14-Kyphoscoliotic Ehlers–Danlos Syndrome

Genes ◽  
2019 ◽  
Vol 10 (7) ◽  
pp. 517 ◽  
Author(s):  
Lim ◽  
Lindert ◽  
Opitz ◽  
Hausser ◽  
Rohrbach ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Protein Trafficking ◽  
Treatment Strategies ◽  
Transcriptome Profiling ◽  
Joint Hypermobility ◽  
Skin Fibroblasts ◽  
Ehlers Danlos Syndrome ◽  
Molecular Features ◽  
Extracellular Matrix Components ◽  
Danlos Syndrome

Kyphoscoliotic Ehlers–Danlos Syndrome (kEDS) is a rare genetic heterogeneous disease clinically characterized by congenital muscle hypotonia, kyphoscoliosis, and joint hypermobility. kEDS is caused by biallelic pathogenic variants in either PLOD1 or FKBP14. PLOD1 encodes the lysyl hydroxylase 1 enzyme responsible for hydroxylating lysyl residues in the collagen helix, which undergo glycosylation and form crosslinks in the extracellular matrix thus contributing to collagen fibril strength. FKBP14 encodes a peptidyl-prolyl cis–trans isomerase that catalyzes collagen folding and acts as a chaperone for types III, VI, and X collagen. Despite genetic heterogeneity, affected patients with mutations in either PLOD1 or FKBP14 are clinically indistinguishable. We aim to better understand the pathomechanism of kEDS to characterize distinguishing and overlapping molecular features underlying PLOD1-kEDS and FKBP14-kEDS, and to identify novel molecular targets that may expand treatment strategies. Transcriptome profiling by RNA sequencing of patient-derived skin fibroblasts revealed differential expression of genes encoding extracellular matrix components that are unique between PLOD1-kEDS and FKBP14-kEDS. Furthermore, we identified genes involved in inner ear development, vascular remodeling, endoplasmic reticulum (ER) stress, and protein trafficking that were differentially expressed in patient fibroblasts compared to controls. Overall, our study presents the first transcriptomics data in kEDS revealing distinct molecular features between PLOD1-kEDS and FKBP14-kEDS, and serves as a tool to better understand the disease.

Inherited defects of connective tissue: Ehlers–Danlos syndrome, Marfan’s syndrome, and pseudoxanthoma elasticum

2010 ◽  
pp. 3771-3787
Author(s):  
N.P. Burrows
Keyword(s):  
Extracellular Matrix ◽  
Connective Tissue ◽  
Collagen Synthesis ◽  
Pseudoxanthoma Elasticum ◽  
Matrix Proteins ◽  
Structural Defects ◽  
Inherited Disorders ◽  
Ehlers Danlos Syndrome ◽  
Synthesis And Processing ◽  
Danlos Syndrome

The inherited disorders of connective tissue are all conditions in which structural defects in collagen or other extra cellular matrix proteins lead to its fragility, with the commonest sites of involvement being the skin, ligaments and vasculature. EDS is a heterogeneous group of disorders resulting from abnormalities in collagen synthesis and processing, or of other extracellular matrix proteins. They can be classified on the basis of descriptive clinical phenotype and/or underlying molecular cause. Most cases are autosomal dominant, but 30 to 50% may be sporadic....

Molecular alterations due to Col5a1 Haploinsufficiency in a mouse model of classic Ehlers Danlos syndrome

2021 ◽  
Author(s):  
Keren Machol ◽  
Urszula Polak ◽  
Monika Weisz-Hubshman ◽  
I-Wen Song ◽  
Shan Chen ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Type I Collagen ◽  
Lysyl Oxidase ◽  
Type I ◽  
Ehlers Danlos Syndrome ◽  
Type V Collagen ◽  
Molecular Alterations ◽  
Extracellular Matrix Components ◽  
Type V ◽  
Danlos Syndrome

Abstract Type V collagen is a regulatory fibrillar collagen essential for type I collagen fibril nucleation and organization and its deficiency leads to structurally abnormal extracellular matrix. Haploinsufficiency of the Col5a1 gene encoding α(1) chain of type V collagen is the primary cause of classic Ehlers Danlos Syndrome (EDS). The mechanisms by which this initial insult leads to the spectrum of clinical presentation is not fully understood. Using transcriptome analysis of skin and Achilles tendons from Col5a1 haploinsufficient (Col5a1+/−) mice, we recognized molecular alterations associated with the tissue phenotypes. We identified dysregulation of extracellular matrix components including thrombospondin-1, lysyl oxidase, and lumican in the skin of Col5a1+/− mice when compared to control. We also identified upregulation of Tgf-β in serum and increased expression of pSmad2 in skin from Col5a1+/− mice suggesting Tgf-β dysregulation as a contributor for abnormal wound healing and atrophic scaring seen in classic EDS. Together, these findings support altered matrix to cell signaling as a component of the pathogenesis of the tissue phenotype in classic EDS and point out potential downstream signaling pathways that may be targeted for treatment of the disease.

Biochemical alterations of uterine leiomyoma extracellular matrix in type IV Ehlers-Danlos syndrome

1999 ◽  
Vol 180 (4) ◽  
pp. 1032-1034 ◽  
Author(s):  
Yanusz Wegrowski ◽  
Georges Bellon ◽  
Christian Quéreux ◽  
François-Xavier Maquart
Keyword(s):  
Extracellular Matrix ◽  
Uterine Leiomyoma ◽  
Ehlers Danlos Syndrome ◽  
Biochemical Alterations ◽  
Type Iv ◽  
Danlos Syndrome

Extracellular matrix and platelet function in patients with musculocontractural Ehlers-Danlos syndrome caused by mutations in theCHST14gene

2012 ◽  
Vol 158A (6) ◽  
pp. 1344-1354 ◽  
Author(s):  
Roberto Mendoza-Londono ◽  
David Chitayat ◽  
Walter H.A. Kahr ◽  
Aleksander Hinek ◽  
Susan Blaser ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Platelet Function ◽  
Ehlers Danlos Syndrome ◽  
Danlos Syndrome

scholarly journals Titin-based stiffening of muscle fibers in Ehlers-Danlos Syndrome

2012 ◽  
Vol 112 (7) ◽  
pp. 1157-1165 ◽  
Author(s):  
Coen A. C. Ottenheijm ◽  
Nicol C. Voermans ◽  
Bryan D. Hudson ◽  
Thomas Irving ◽  
Ger J. M. Stienen ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Muscle Weakness ◽  
Muscle Protein ◽  
Muscle Fibers ◽  
Calcium Sensitivity ◽  
Passive Tension ◽  
Active Tension ◽  
Ehlers Danlos Syndrome ◽  
Activation Level ◽  
Danlos Syndrome

Objective: tenascin-X (TNX) is an extracellular matrix glycoprotein whose absence leads to Ehlers-Danlos Syndrome (EDS). TNX-deficient EDS patients present with joint hypermobility and muscle weakness attributable to increased compliance of the extracellular matrix. We hypothesized that in response to the increased compliance of the extracellular matrix in TNX-deficient EDS patients, intracellular adaptations take place in the elastic properties of the giant muscle protein titin. Methods: we performed extensive single muscle fiber mechanical studies to determine active and passive properties in TNX-deficient EDS patients. Gel-electrophoresis, Western blotting, and microarray studies were used to evaluate titin expression and phosphorylation. X-ray diffraction was used to measure myofilament lattice spacing. Results: passive tension of muscle fibers from TNX-deficient EDS patients was markedly increased. Myofilament extraction experiments indicated that the increased passive tension is attributable to changes in the properties of the sarcomeric protein titin. Transcript and protein data indicated no changes in titin isoform expression. Instead, differences in posttranslational modifications within titin's elastic region were found. In patients, active tension was not different at maximal activation level, but at submaximal activation level it was augmented attributable to increased calcium sensitivity. This increased calcium sensitivity might be attributable to stiffer titin molecules. Conclusion: in response to the increased compliance of the extracellular matrix in muscle of TNX-deficient EDS patients, a marked intracellular stiffening occurs of the giant protein titin. The stiffening of titin partly compensates for the muscle weakness in these patients by augmenting submaximal active tension generation.

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