Materiały źródłowe

• #1 Molecular Genetics and Pathogenesis of Ehlers–Danlos Syndrome and Related Connective Tissue Disorders

  https://www.mdpi.com/2073-4425/11/5/547

  Ehlers–Danlos syndromes (EDS) are a group of heritable connective tissue disorders (HCTDs) characterized by a variable degree of skin hyperextensibility, joint hypermobility and tissue fragility. The current EDS classification distinguishes 13 subtypes and 19 different causal genes mainly involved in collagen and extracellular matrix synthesis and maintenance. […] The major challenging task in EDS today is to unravel the molecular basis of the most frequent EDS type, namely hypermobile EDS (hEDS), the diagnosis of which remains reliant on clinical findings for the absence of any definite laboratory test. This EDS subtype as well as other EDS-reminiscent phenotypes are currently investigated worldwide to unravel the primary genetic defect and related pathomechanisms. […] The authors review their previous transcriptome and protein studies on patient dermal fibroblasts, emphasizing that these cells, despite sharing a common ECM remodeling, show differences in the underlying pathomechanisms. In cEDS and vEDS fibroblasts, key processes such as collagen biosynthesis/processing, protein folding quality control, endoplasmic reticulum (ER) homeostasis, autophagy, and wound healing emerged as perturbed. In hEDS cells, gene expression changes related to cell–matrix interactions, inflammatory/pain responses, and the acquisition of an in vitro pro-inflammatory myofibroblast-like phenotype seem to contribute to the complex pathogenesis of this molecularly unsolved EDS type. […] The evidence that the application of untargeted general omics approaches may serve as a valuable tool to identify novel proteins or pathways involved in the pathogenesis of the different EDS types is also documented in the original research article by Lim et al.

• #2 Molecular Genetics and Pathogenesis of Ehlers–Danlos Syndrome and Related Connective Tissue Disorders

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7288446/

  EhlersDanlos syndromes (EDS) are a group of heritable connective tissue disorders (HCTDs) characterized by a variable degree of skin hyperextensibility, joint hypermobility and tissue fragility. […] Currently, the major challenging task in EDS is to unravel the molecular basis of the hypermobile EDS that is the most frequent form, and for which the diagnosis is only clinical in the absence of any definite laboratory test. […] The major challenging task in EDS today is to unravel the molecular basis of the most frequent EDS type, namely hypermobile EDS (hEDS), the diagnosis of which remains reliant on clinical findings for the absence of any definite laboratory test. […] Understanding the genetic pathways and etiopathomechanisms leading to hEDS will advise the search for possible therapeutic approaches for this disorder.

• #3 Ehlers-Danlos syndromes: Clinical manifestations and diagnosis – UpToDate

  https://www.uptodate.com/contents/ehlers-danlos-syndromes-clinical-manifestations-and-diagnosis

  The pathogenesis, clinical manifestations, diagnosis, and differential diagnosis of the major forms of EDS will be presented here. […] While the genetic basis for most types of EDS has been defined, the most common form, hypermobile EDS (hEDS), remains elusive to molecular diagnosis. […] Ehlers-Danlos syndromes classification and pathogenesis.

• #4 Genetics of Ehlers-Danlos Syndrome: Practice Essentials, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/943567-overview

  Individuals with Ehlers-Danlos syndrome (EDS) demonstrate connective-tissue abnormalities due to defects in the inherent strength, elasticity, integrity, and healing properties of the tissues. […] Ehlers-Danlos syndrome (EDS) is caused by various abnormalities in the synthesis and metabolism of collagen and other connective-tissue proteins in the ECM, such as elastin, proteoglycans, and macromolecular proteins. […] Collagen is the most abundant protein in the body and is the most common protein found in the ECM. […] Elastin allows for the tissues to stretch and return to their original state and hence is present in the ECM of blood vessels, lungs, and skin. […] Proteoglycans are core proteins that are bound to glycosaminoglycans (also commonly termed mucopolysaccharides). Essentially, proteoglycans are the glue of the connective-tissue protein that seal and cement the underlying connective-tissue matrix.

• #5 Ehlers-Danlos syndrome: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/ehlers-danlos-syndrome/

  Ehlers-Danlos syndrome is a group of disorders that affect connective tissues supporting the skin, bones, blood vessels, and many other organs and tissues. Defects in connective tissues cause the signs and symptoms of these conditions, which range from mildly loose joints to life-threatening complications. […] Variants (also known as mutations) in at least 20 genes have been found to cause the Ehlers-Danlos syndromes. Variants in the COL5A1 or COL5A2 gene, or rarely in the COL1A1 gene, can cause the classical type. Variants in the TNXB gene cause the classical-like type and have been reported in a very small percentage of cases of the hypermobile type (although in most people with this type, the cause is unknown). The cardiac-valvular type and some cases of the arthrochalasia type are caused by COL1A2 gene variants; variants in the COL1A1 gene have also been found in people with the arthrochalasia type. Most cases of the vascular type result from variants in the COL3A1 gene, although rarely this type is caused by certain COL1A1 gene variants. The dermatosparaxis type is caused by variants in the ADAMTS2 gene. PLOD1 or FKBP14 gene variants result in the kyphoscoliotic type. Other rare forms of Ehlers-Danlos syndrome result from variants in other genes.

• #6 Ehlers–Danlos syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Ehlers%E2%80%93Danlos_syndrome

  Ehlers-Danlos syndromes (EDS) is a group of 14 genetic connective-tissue disorders. Symptoms often include loose joints, joint pain, stretchy velvety skin, and abnormal scar formation. These may be noticed at birth or in early childhood. Complications may include aortic dissection, joint dislocations, scoliosis, chronic pain, or early osteoarthritis. The existing classification was last updated in 2017, when a number of rarer forms of EDS were added. […] EDS occurs due to mutations in one or more particular genes; there are 19 genes that can contribute to the condition. The specific gene affected determines the type of EDS, though the genetic causes of hypermobile Ehlers-Danlos syndrome are still unknown. Some cases result from a new variation occurring during early development, while others are inherited in an autosomal dominant or recessive manner. Typically, these variations result in defects in the structure or processing of the protein collagen or tenascin.

• #7 Ehlers–Danlos syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Ehlers%E2%80%93Danlos_syndrome

  Variations in these genes usually alter the structure, production, or processing of collagen or proteins that interact with collagen. Collagen provides structure and strength to connective tissue. A defect in collagen can weaken connective tissue in the skin, bones, blood vessels, and organs, resulting in the features of the disorder. Inheritance patterns depend on the specific syndrome. […] Most forms of EDS are inherited in an autosomal dominant pattern, which means only one of the two copies of the gene in question must be altered to cause a disorder. A few are inherited in an autosomal recessive pattern, which means both copies of the gene must be altered for a person to be affected. It can also be an individual (de novo or „sporadic”) variation. Sporadic variations occur without any inheritance.

• #8

  https://www.jci.org/articles/view/12881

  The concept that EDS is a disorder of fibrillar collagen metabolism is well supported by identification of specific defects in the collagen biosynthetic pathway that produce clinically distinct forms of EDS. There are three fundamental mechanisms of disease known to produce EDS: deficiency of collagen-processing enzymes, dominant-negative effects of mutant collagen chains, and haploinsufficiency. The two known examples of deficient enzyme activity leading to EDS are lysyl-hydroxylase deficiency and procollagen peptidase deficiency. In both circumstances the morphology and strength of the collagen fibril is compromised, explaining the severe and early clinical findings. […] Dominant-negative mutations in collagen I, III, and V cause several different forms of EDS. The most clinically significant of these are COL3A1 mutations causing the potentially lethal vascular form of EDS. The reported COL3A1 mutations are either exon-skipping mutations or missense mutations that disrupt the collagen triple helix.

• #9 Molecular insights in the pathogenesis of classical Ehlers-Danlos syndrome from transcriptome-wide expression profiling of patients’ skin fibroblasts | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0211647

  More than 90% of cEDS patients harbor a pathogenic variant in the COL5A1 and COL5A2 genes encoding type V collagen (COLLV). […] COLLV haploinsufficiency is the most common molecular defect caused by a non-functional COL5A1 allele, whereas variants in COL5A2 affect its structural integrity and are generally associated with a more severe phenotype. […] The majority of pathogenetic variants in COL5A1 are nonsense, frameshift or splice site mutations that generate a premature termination codon, with the consequent activation of the nonsense-mediated mRNA decay pathway, finally leading to COLLV haploinsufficiency. […] Conversely, almost all described disease-causing variants in COL5A2 are missense or in-frame exon-skipping splice mutations, which result in the production of mutant 2(V) chains that exert a dominant negative effect on COLLV molecules.

• #10 Clinical and genetic aspects of Ehlers-Danlos syndrome, classic type | Genetics in Medicine

  https://www.nature.com/articles/gim2010100

  Classic Ehlers-Danlos syndrome is a heritable connective tissue disorder characterized by skin hyperextensibility, fragile and soft skin, delayed wound healing with formation of atrophic scars, easy bruising, and generalized joint hypermobility. […] It is currently estimated that approximately 50% of patients with a clinical diagnosis of classic Ehlers-Danlos syndrome harbor mutations in the COL5A1 and the COL5A2 gene, encoding the 1 and the 2-chain of type V collagen, respectively. […] In the majority of patients with molecularly characterized classic Ehlers-Danlos syndrome, the disease is caused by a mutation leading to a nonfunctional COL5A1 allele and resulting in haploinsufficiency of type V collagen. […] Most mutations identified so far result in a reduced amount of type V collagen in the connective tissues available for collagen fibrillogenesis.

• #11 Clinical and genetic aspects of Ehlers-Danlos syndrome, classic type | Genetics in Medicine

  https://www.nature.com/articles/gim2010100

  The COL5A1 gene, located at 9q34.2-q34.3, is a large gene, comprising 66 exons distributed over 150 kb of gDNA, and it encodes the 1 chain of type V collagen. […] The most common types of molecular defect lead to haploinsufficiency for the COL5A1 mRNA. […] In approximately one third of individuals with classic EDS, nonsense or frameshift mutations are responsible for a nonfunctional COL5A1 allele. […] Structural mutations in the COL5A1, which exert a dominant-negative effect, have been demonstrated in a few individuals with classic EDS. […] These structural mutations are most commonly splice site mutations that result in exon skipping and a few point mutations that result in the substitution for glycine in the triple-helical region of the collagen molecule. […] Two COL5A1 mutations have been reported deleting one or more highly conserved cysteine residues in the C-terminal propeptide of the 1(V) collagen chain, which are essential for intrachain disulphide bonding before assembly of the pro-chains and initiation of triple-helix folding of fibrillar collagen molecules.

• #12 Molecular insights in the pathogenesis of classical Ehlers-Danlos syndrome from transcriptome-wide expression profiling of patients’ skin fibroblasts | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0211647

  Molecular insights in the pathogenesis of classical Ehlers-Danlos syndrome from transcriptome-wide expression profiling of patients skin fibroblasts […] Classical Ehlers-Danlos syndrome (cEDS) is a dominant inherited connective tissue disorder mainly caused by mutations in the COL5A1 and COL5A2 genes encoding type V collagen (COLLV), which is a fibrillar COLL widely distributed in a variety of connective tissues. […] Most of the causative variants result in a non-functional COL5A1 allele and COLLV haploinsufficiency, whilst COL5A2 mutations affect its structural integrity. […] To shed light into disease mechanisms involved in cEDS, we performed gene expression profiling in skin fibroblasts from four patients harboring haploinsufficient and structural mutations in both disease genes. […] These gene expression changes are consistent with our previous protein findings on in vitro fibroblasts from other cEDS patients, which exhibited reduced migration and poor wound repair owing to COLLV disorganization, altered deposition of fibronectin into ECM, and an abnormal integrin pattern. […] Our findings provide the first molecular evidence of significant gene expression changes in cEDS skin fibroblasts highlighting that defective ECM remodeling, ER homeostasis and autophagy might play a role in the pathogenesis of this connective tissue disorder.

• #13 Ehlers-Danlos Syndrome: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/1114004-overview

  Ehlers-Danlos syndrome (EDS) is a heterogeneous group of inherited connective-tissue disorders characterized by joint hypermobility, cutaneous fragility, and hyperextensibility. The collagen defect has been identified in at least six of the many types of Ehlers-Danlos syndrome. The vascular form, sometimes referred to as type IV, is characterized by a decreased amount of type III collagen. It is autosomal dominant and caused by mutations in the COL3A1 gene that result in increased fragility of connective tissue with arterial, intestinal, and uterine ruptures and premature death. […] Types V and VI are characterized by deficiencies in hydroxylase and lysyl oxidase, an important posttranslational modifying enzyme in collagen biosynthesis. Type VII has an amino-terminal procollagen peptidase deficiency. Type IX has abnormal copper metabolism. Type X has nonfunctioning plasma fibronectin.

• #14 The Ehlers-Danlos Syndromes — Clover Genetics

  https://clovergenetics.com/the-ehlersdanlos-syndromes

  Vascular EDS is often considered the most severe form of EDS due to the risk for fatal arterial rupture and other serious complications. […] Collagen III is the gene implicated in vEDS and compared to collagen I, it produces small-diameter fibrils that comprise about 5-20% of all human collagen and provides tensile strength and integrity to the major blood vessels of the hollow organs. […] Cardiac-valvular EDS is an extremely rare form of EDS, as of 2017 there were an estimated six patients identified with documented biallelic autosomal recessive variants in COL1A2. […] This condition is very rare and is caused by changes in the ADAMTS2 gene. […] Molecular testing of the Collagen 12 gene is required for confirmatory testing.

• #15 Survival is affected by mutation type and molecular mechanism in vascular Ehlers–Danlos syndrome (EDS type IV) | Genetics in Medicine

  https://www.nature.com/articles/gim201472

  Missense and splice-site mutations accounted for more than 90% of the 572 alterations that we had identified in COL3A1. […] Although vascular Ehlers-Danlos syndrome appears to be genetically homogeneous, allelic heterogeneity is marked, and the natural history varies with gender and type of mutation in COL3A1. […] Individuals with vEDS and mutations in COL3A1 have, on average, a diminished life span. […] We identified several different classes of mutations that included missense alterations (substitutions for glycine residues in the triple helical tripeptide Gly-X-Y repeat region), premature termination codons, and splice donor and splice acceptor site alterations. […] Families with null mutations that result in either mRNA instability or pro1(III) chain instability have the longest survival of all individuals with COL3A1 mutations.

• #16

  https://omim.org/entry/130050

  A number sign (#) is used with this entry because vascular-type Ehlers-Danlos syndrome (EDSVASC) is caused by heterozygous mutation in the COL3A1 gene (120180) on chromosome 2q32. […] Biallelic mutation in the COL3A1 gene causes polymicrogyria with or without vascular EDS (PMGVEDS; 618343). […] The vascular type of Ehlers-Danlos syndrome is characterized by the major complications of arterial and bowel rupture, uterine rupture during pregnancy, and the clinical features of easy bruising, thin skin with visible veins, and characteristic facial features (summary by Leistritz et al., 2011). […] Type III procollagen is stored in dermal fibroblasts which show markedly dilated endoplasmic reticulum. […] Probably a defect in type III collagen is a common feature. […] Chemical studies showed striking deficiency of type III collagen in all 3 cases.

• #17

  https://www.jci.org/articles/view/130730

  Vascular Ehlers-Danlos syndrome (vEDS) is an autosomal-dominant connective tissue disorder caused by heterozygous mutations in the COL3A1 gene, which encodes the pro-1 chain of collagen III. […] Loss of structural integrity of the extracellular matrix is believed to drive the signs and symptoms of this condition, including spontaneous arterial dissection and/or rupture, the major cause of mortality. […] We showed that signaling abnormalities in the PLC/IP3/PKC/ERK pathway (phospholipase C/inositol 1,4,5-triphosphate/protein kinase C/extracellular signal-regulated kinase) are major mediators of vascular pathology. […] Taken together, our results provide evidence that targetable signaling abnormalities contribute to the pathogenesis of vEDS, highlighting unanticipated therapeutic opportunities.

• #18

  https://www.jci.org/articles/view/130730

  The current understanding of this condition is that reduced amounts of collagen III cause loss of structural integrity of the tissues, which directly leads to the tissue fragility and failure in vEDS. […] We propose what we believe to be a novel understanding of vEDS pathogenesis, in which the risk of vascular rupture is mediated by excessive signaling through the PLC/IP3/PKC/ERK axis. […] This model is supported by unbiased expression profiling of a vulnerable segment of the aortic wall in vEDS mice and by the phenotypic rescue observed upon pharmacologic attenuation of IP3 (hydralazine), PKC (ruboxistaurin), or MEK/ERK (cobimetinib), establishing that increased phosphorylation is a cause (and not simply a consequence) of the pathology. […] Our results provide the first evidence for a targetable signaling abnormality that contributes to the pathogenesis of vEDS and illustrate the promise of therapeutic strategies aimed at inhibition of the PLC/IP3/PKC/ERK axis of activation.

• #19 Hypermobile Ehlers-Danlos Syndrome and Hypermobility Spectrum Disorders | AAFP

  https://www.aafp.org/pubs/afp/issues/2021/0415/p481.html

  Hypermobile EDS is the only EDS subtype for which a genetic mutation has not been discovered. Hypermobile EDS is considered to be inherited in an autosomal dominant manner with incomplete penetrance. The pathogenesis of hypermobile EDS and hypermobility spectrum disorders is still being unraveled but involves muscle and tendon laxity, reduced proprioception, significantly disordered connective tissue structure, and alterations in gene expression. […] Ehlers-Danlos syndromes (EDS) are a group of inherited connective tissue disorders caused by abnormalities in the structure, production, and/or processing of collagen. The new classification, from 2017, includes 13 subtypes of EDS. Joint hypermobility is a feature common among many EDS subtypes and other heritable connective tissue disorders. Joint hypermobility is defined as the ability of a joint to move beyond normal limits along physiological axes. Joint hypermobility can involve a few or many joints and may be entirely asymptomatic. Generalized joint hypermobility is more likely to be associated with a genetic syndrome than localized joint hypermobility. The exception is hypermobile EDS, which is the most common EDS variant, representing 80% to 90% of EDS cases, with clinical features including joint hypermobility, skin findings, and joint pains or recurrent dislocations.

• #20 Cellular and Molecular Mechanisms in the Pathogenesis of Classical, Vascular, and Hypermobile Ehlers‒Danlos Syndromes

  https://www.mdpi.com/2073-4425/10/8/609

  The Ehlers-Danlos syndromes (EDS) constitute a heterogenous group of connective tissue disorders characterized by joint hypermobility, skin abnormalities, and vascular fragility. The latest nosology recognizes 13 types caused by pathogenic variants in genes encoding collagens and other molecules involved in collagen processing and extracellular matrix (ECM) biology. Classical (cEDS), vascular (vEDS), and hypermobile (hEDS) EDS are the most frequent types. cEDS and vEDS are caused respectively by defects in collagen V and collagen III, whereas the molecular basis of hEDS is unknown. For these disorders, the molecular pathology remains poorly studied. Herein, we review, expand, and compare our previous transcriptome and protein studies on dermal fibroblasts from cEDS, vEDS, and hEDS patients, offering insights and perspectives in their molecular mechanisms. These cells, though sharing a pathological ECM remodeling, show differences in the underlying pathomechanisms. In cEDS and vEDS fibroblasts, key processes such as collagen biosynthesis/processing, protein folding quality control, endoplasmic reticulum homeostasis, autophagy, and wound healing are perturbed. In hEDS cells, gene expression changes related to cell-matrix interactions, inflammatory/pain responses, and acquisition of an in vitro pro-inflammatory myofibroblast-like phenotype may contribute to the complex pathogenesis of the disorder. Finally, emerging findings from miRNA profiling of hEDS fibroblasts are discussed to add some novel biological aspects about hEDS etiopathogenesis.

• #21 Norris Lab Researchers Discover Hypermobile EDS Gene | The EDS Clinic

  https://www.eds.clinic/articles/norris-lab-researchers-discover-hypermobile-eds-gene

  Hypermobile Ehlers-Danlos syndrome (hEDS) is a prevalent hereditary connective tissue disorder characterized by joint hypermobility, tissue fragility, and multi-organ involvement. […] Recent research has unveiled a critical breakthrough: the identification of variants in the Kallikrein gene family, particularly KLK15, which are implicated in the pathogenesis of hEDS. […] A comprehensive study involving whole exome sequencing (WES) of families with hEDS and a cohort of sporadic patients revealed a missense variant in the Kallikrein-15 gene (KLK15 p.Gly226Asp). This pivotal finding underscores the role of Kallikrein gene variants in hEDS and marks a significant step towards earlier diagnosis and improved clinical outcomes. […] The discovery of KLK15 and other Kallikrein gene variants in hEDS patients is groundbreaking for several reasons: Enhanced Understanding of Pathogenesis: This research provides the first genetic and biological evidence linking Kallikrein gene variants to hEDS, offering new insights into the molecular mechanisms underlying the disease. […] The identification of Kallikrein gene variants, particularly KLK15, in the pathogenesis of hypermobile Ehlers-Danlos syndrome represents a monumental step forward in both scientific research and patient care.

• #22 Pathogenesis of EDS/HSD research | hEDS Together

  https://hedstogether.com/projects/pathogenesis-eds-hsd/

  Fibroblasts play an important role controlling the integrity of the connective tissue via a mechanism called tensional homeostasis. This involves fibroblasts pulling on collagen to adjust the tension within the connective tissue to maintain it at normal levels. This ability depends on two key features of fibroblasts: cell adhesion to collagen and cytoskeleton dynamics. […] Previously published experiments with EDS fibroblasts from animals found that they had a reduced cell adhesion to collagen, which caused a failure of the tensional homeostasis mechanism and resulted in fragile connective tissue in EDS animals. […] We further highlight how human EDS fibroblasts show equivalent impairments in cell adhesion (i.e. the integrin switch) to the fibroblasts from EDS animals, which was the specific molecular defect responsible for the failure of tensional homeostasis in EDS animals.

• #23 The role of cell adhesion and cytoskeleton dynamics in the pathogenesis of the Ehlers-Danlos syndromes and hypermobility spectrum disorders – WRAP: Warwick Research Archive Portal

  https://wrap.warwick.ac.uk/id/eprint/151120/

  The Ehlers-Danlos Syndromes (EDS) are a group of 13 disorders, clinically defined through features of joint hypermobility, skin hyperextensibility, and tissue fragility. Most subtypes are caused by mutations in genes affecting the structure or processing of the extracellular matrix (ECM) protein collagen. […] The pathogenesis of all these disorders however, remains poorly understood. […] The defective ECM however, also has consequences on cellular processes. EDS/HSD fibroblasts exhibit a dysfunctional phenotype including impairments in cell adhesion and cytoskeleton organization, though the pathological significance of this has remained unclear. […] Recent advances in our understanding of fibroblast mechanobiology however, suggests these changes may actually reflect features of a pathomechanism we herein define. […] We propose that EDS/HSD may be a disorder of membrane-bound collagen, and consider how aberrations in cell adhesion and cytoskeletonal dynamics could drive the abnormal properties of the connective tissue, and may even be responsible for the pathogenesis of EDS/HSD.

• #24 EDS biology blog 2: The molecular changes in EDS/HSD fibroblasts | hEDS Together

  https://hedstogether.com/eds-hsd-fibroblasts/

  Studies looking at the fibroblasts of EDS/HSD patients found that they also show abnormalities. The most consistent change found across all EDS/HSD subtypes involves integrins. […] EDS/HSD fibroblasts undergo something called an integrin switch. Here, the collagen receptor (the 21 integrin) becomes internalised by the fibroblast and no longer sits on the surface. A receptor for fibronectin (the v3 integrin) is upregulated, and this integrin sits on the surface of EDS/HSD fibroblasts instead. […] This integrin switch occurs because collagen had not interacted with its 21 receptor in some way, most likely due to some structural defect in collagen. In response to this, fibroblasts decide to attach to a different ECM protein, like fibronectin, and so upregulate the v3 integrin instead. […] While these molecular changes are interesting, scientists do not currently understand exactly what this means or how this might contribute to weak connective tissue.

• #25 Pathogenesis of EDS/HSD research | hEDS Together

  https://hedstogether.com/projects/pathogenesis-eds-hsd/

  We therefore propose that the same failures in tensional homeostasis occur in human EDS/HSD patients, and that further investigations are now required to test whether this is the principal mechanism responsible for EDS/HSD pathogenesis. […] We hypothesise that EDS/HSD could be a disorder of membrane-bound collagen, which occurs when fibroblasts can no longer attach to collagen. Their failure to then adequately implement the tensional homeostasis mechanism is what may then cause the abnormal connective tissue in EDS/HSD.

• #26 Molecular insights in the pathogenesis of classical Ehlers-Danlos syndrome from transcriptome-wide expression profiling of patients’ skin fibroblasts | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0211647

  Patients cells also showed decreased mRNA levels of several ECM-associated genes including SPP1, POSTN, and EDIL3, which encode matricellular proteins primarily acting as mediators of cell-matrix interactions rather than as structural components. […] Finally, in cEDS fibroblasts biological functions related to intracellular protein transport, endoplasmic reticulum (ER) proteostasis, and autophagy seem to be perturbed, as suggested by the reduced transcription of many related genes such as DNAJB7, RAB33A, VPS29, CCPG1, ATG10, SVIP, and VIPAS39. […] In conclusion, our approach illustrates global mRNA profiling changes of several genes and related biological processes that could offer novel insights in the cEDS pathophysiology. Additional functional work is required to verify whether altered ER proteostasis and defective autophagy play a crucial role in the pathogenesis of this connective tissue disorder, thus offering future therapeutic options.

• #27 Cellular and Molecular Mechanisms in the Pathogenesis of Classical, Vascular, and Hypermobile Ehlers‒Danlos Syndromes

  https://www.mdpi.com/2073-4425/10/8/609

  The decrease in the tensile strength and integrity of skin, joints, and hollow organs is a common disease mechanism shared by the different EDS types. This mechanical weakness is considered the driving factor of connective tissue fragility, even if it is likely that multiple cell-matrix interplays and involvement of distinct intracellular signaling pathways contribute to the molecular pathology of the different EDS phenotypes. […] Taken together, these studies highlighted that the alteration of the ECM structural integrity is a common disease factor contributing to the pathogenesis of all these conditions. In cEDS and vEDS fibroblasts, the ECM disarray is a direct consequence of molecular defects in respectively collagen V and collagen III that impair common molecular functions essential to guarantee adequate folding and maturation of proteins and biological processes crucial for cell survival and homeostasis. The ECM disorganization observed in hEDS cells may be a consequence of an excessive pathological turnover, mainly due to ECM-degrading enzymes and other so far unknown factors, which might be primary contributors involved in the transition to a pro-inflammatory myofibroblast-like phenotype. Consistently, the perturbation of distinct transcriptional patterns observed in cEDS, vEDS, and hEDS fibroblasts pointed out different disease mechanisms underlying the pathophysiology of these EDS cell types.

• #28 Cellular and Molecular Mechanisms in the Pathogenesis of Classical, Vascular, and Hypermobile Ehlers‒Danlos Syndromes

  https://www.mdpi.com/2073-4425/10/8/609

  The pathological consequences of defects in ECM components depend on the balance between extracellular effects, e.g., reduced protein secretion and export of misfolded proteins, and intracellular consequences such as apoptosis activation, ER dysfunction, and autophagy perturbation that impact in different ways on the molecular pathology and disease severity.

• #29 Ehlers-Danlos Syndrome: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/1114004-overview

  Transmission electron micrographs of type I collagen fibrils in a proband dermal biopsy specimen demonstrated heterogeneity in fibril diameter that was greater than that of a matched control sample. […] The proband was found to have a greater proportion of both larger and smaller fibrils, and occasional fibrils with a cauliflower configuration were observed. […] Wenstrup and associates identified haploinsufficiency of the COL5A1 gene that encodes the proalpha1(V) chain of type V collagen in the classic form of Ehlers-Danlos syndrome. […] Eight of 28 probands with classic Ehlers-Danlos syndrome who were heterozygous for expressed polymorphisms in COL5A1 had complete or nearly complete loss of expression of one COL5A1 allele. […] One third of individuals with classic Ehlers-Danlos syndrome were estimated to have mutations of COL5A1 that result in haploinsufficiency.

• #30 SciELO Brazil – Classical Ehlers-Danlos syndrome: clinical, Histological and ultrastructural aspects Classical Ehlers-Danlos syndrome: clinical, Histological and ultrastructural aspects

  https://www.scielo.br/j/abd/a/RL6VNN7JytsKxC43m9mH3ZQ/

  The central pathogenesis of Ehlers-Danlos syndrome (EDS) results from defects in collagen. Mutations were identified in structural collagen genes, as well as in genes coding for proteins involved in the processing of this protein. […] The hypothesis that EDS is a disorder of fibrillar collagen metabolism is well supported by the identification of specific defects in the collagen biosynthetic pathway that result in clinically different EDS forms. […] Three fundamental mechanisms of disease are known to produce EDS: a deficiency of collagen-processing enzymes, dominant negative effects of mutant collagen alpha-chains and haploinsufficiency. […] These histological and ultrastructural findings are similar to those found in the literature and help to elucidate the pathogenesis of this classical dermatological condition.

• #31 Shaping the future of care for patients with Ehlers-Danlos syndromes: from multidisciplinary management to precision medicine | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-025-03615-5

  Ehlers-Danlos syndromes (EDS) are a group of hereditary connective tissue disorders (HCTDs) with considerable clinical and genetic heterogeneity. To date, 21 genes have been associated with EDS; however, the genetic basis of the most prevalent subtype hypermobile EDS remains unknown. […] Recent studies have further revealed several continuous phenotypic spectra, including hypermobility spectrum disorders, COL1-related overlap disorder, and linkeropathies, involving various EDS subtypes. […] In recent years, scientific exchange on EDS has increased unprecedentedly, with a growing focus on molecular finding-guided management strategies. Surgical planning and long-term monitoring of vascular comorbidities in vEDS are gradually shifting toward genotype-guided approaches. For example, variants leading to haploinsufficiency are typically associated with milder manifestations, while glycine substitutions in the triple helix region or splicing variants are linked to a more aggressive disease course.

• #32 Ehlers-Danlos Syndrome – Rheumatology Advisor

  https://www.rheumatologyadvisor.com/ddi/ehlers-danlos-syndrome/

  Patients with Ehlers-Danlos syndrome can develop serious complications, including major articular complications such as subluxation and dislocation of the joints (shoulder, patella, digits, hip, radius, and clavicles) and chronic joint and limb pain. Individuals with a severe form of classic Ehlers-Danlos syndrome or vascular Ehlers-Danlos syndrome could experience life-threatening rupture of large arteries, intracranial aneurysms, and arteriovenous fistulas.

• #33 Shaping the future of care for patients with Ehlers-Danlos syndromes: from multidisciplinary management to precision medicine | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-025-03615-5

  Emerging investigations using advanced technologies are uncovering mechanistic insights that pave the way for novel targeted therapies across various EDS subtypes. For example, inhibition of integrin signaling or injection of wild-type fibroblasts into Col5a1CKO mice improved poor wound healing, a hallmark feature of cEDS. […] Diverse in vitro and in vivo models, such as animal models, cell lines, and patient-derived induced pluripotent stem cells, have been established to explore the etiology, pathophysiology, and pathogenesis of nearly every rare subtype of EDS, opening new possibilities for future therapeutic strategies.

• #34 hEDS & HSD Research: The Search for Causes and Diagnostic Tests – The Ehlers Danlos Society

  https://www.ehlers-danlos.com/heds-hsd-research/

  Hypermobile EDS (hEDS) remains the only type of the thirteen classified Ehlers-Danlos syndromes that cannot be confirmed through a genetic test. The genes associated with hEDS are currently unknown, and diagnosis is made on a clinical basis. […] If we can achieve a better understanding of the underlying genetics and the gene expression abnormalities, we may be able to develop diagnostic tests and find more specific treatments for hypermobile EDS and, potentially, the hypermobility spectrum disorders. […] Insights into the mechanisms that cause disease in hypermobile EDS (hEDS) remain scarce. An important reason for this is the huge variation in clinical presentation among hEDS patients, which makes it unlikely that a single genetic defect will be responsible to cause this condition, but at the same time, it also makes it hard to pinpoint the exact molecular cause. Nevertheless, given the overlap of clinical symptoms with other EDS subtypes, that lead to abnormalities in the extracellular matrix (ECM), especially with classical EDS (cEDS), it is likely that the mechanisms underlying hEDS also affect the ECM to a certain extent.

• #35 Ehlers-Danlos Syndromes: Symptoms, Treatment, and Types

  https://patient.info/bones-joints-muscles/ehlers-danlos-syndrome-leaflet

  The main risk that people with vEDS face is leaking or bursting (rupture) of medium/large arteries. There is also a small risk of rupture of the large bowel (colon), and of the womb (uterus) during labour, and of spontaneous pneumothorax (caused by popping of an air space in the lungs). These are life-threatening effects, which usually occur in young adulthood, making this an extremely difficult diagnosis to be given. […] Treatment with a medicine called celiprolol greatly reduces the risk of arterial rupture. It may also be possible to repair blood vessels at risk of rupture before they do. This is a very specialised area.

• #36 Ehlers-Danlos syndromes: state of the art on clinical practice guidelines | RMD Open

  https://rmdopen.bmj.com/content/4/Suppl_1/e000790

  Elucidation of the pathogenesis of features impacting the quality of life of the affected individuals might increase medical care. […] Future research should focus on the elucidation of the pathogenesis of features impacting quality of life of the affected individuals, diagnosis and progression at different ages, and on the identification of clinically reliable biomarkers and targetable signalling pathways and cellular processes for possible personalised therapies. […] In September 2018, The International Symposium on the EDS in Ghent Belgium reviewed the state-of-the-art and the new research on clinical advances and the molecular and pathogenic mechanisms underlying EDS, and related syndromes were discussed attempting to reach at least some areas of the unmet needs.

• #37 hEDS & HSD Research: The Search for Causes and Diagnostic Tests – The Ehlers Danlos Society

  https://www.ehlers-danlos.com/heds-hsd-research/

  The findings resulting from this research will be helpful to understand the defective mechanisms in hEDS, but also in cEDS. Moreover, this approach may result in the identification of (a) prognostic biomarker(s) for disease progression and the development of complications, such as chronic widespread pain or other symptoms. […] The present proposal aims to unravel, by integrated molecular, biochemical/physical, and nanoscience approaches, bioactive key molecules, and pathophysiological mechanisms associated with these conditions. […] This research, followed by targeted in vivo translational studies on patients serum/plasma, should contribute to the elucidation of the etiopathogenesis of hEDS and HSD, offer the possibility to identify potential biomarkers defining whether these disorders are part of a phenotypic spectrum rather than distinct clinical entities and, ultimately, pave the way to the development of targeted therapeutic strategies with a potential benefit for patients management.

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