C1R Mutations Trigger Constitutive Complement 1 Activation in Periodontal Ehlers-Danlos Syndrome

We report extensive functional studies of 16 C1R variants associated with pEDS by in-vitro overexpression studies in HEK293T cells followed by western blot, size exclusion chromatography and surface plasmon resonance analyses. Patient-derived skin fibroblasts were analyzed by western blot and Enzyme-linked Immunosorbent Assay (ELISA). Overexpression of C1R variants in HEK293T cells revealed that none of the pEDS variants was integrated into the C1 complex but cause extracellular presence of catalytic C1r/C1s activities. Variants showed domain-specific abnormalities of intracellular processing and secretion with preservation of serine protease function in the supernatant. In contrast to C1r wild type, and with the exception of a C1R missense variant disabling a C1q binding site, pEDS variants had different impact on the cell: retention of C1r fragments inside the cell, secretion of aggregates, or a new C1r cleavage site. Overexpression of C1R variants in HEK293T as well as western blot analyses of patient fibroblasts showed decreased levels of secreted C1r. Importantly, all available patient fibroblasts exhibited activated C1s and activation of externally added C4 in the supernatant while control cell lines secreted proenzyme C1s and showed no increase in C4 activation. The central elements in the pathogenesis of pEDS seem to be the intracellular activation of C1r and/or C1s, and extracellular presence of activated C1s that independently of microbial triggers can activate the ...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research

Related Links:

Publication date: Available online 26 September 2020Source: International Journal of Surgery Case ReportsAuthor(s): Oliver Scheufler, Julian Ramin Andresen, Reimer Andresen
Source: International Journal of Surgery Case Reports - Category: Surgery Source Type: research
General examination – eyes and facial dysmorphism Clinically examination is guided by the symptoms. Unless the history is not correlated with findings, important diagnostic possibilities may be missed. Clinical examination starts off with a focused general examination followed by a detailed examination of the cardiovascular system. Relevant points in other systems like basal crepitations, hepatosplenomegaly and neurological deficits should be looked for. Examination strategy should be fitting to the clinical situation. When a patient presents to the emergency room, it should be a short but focused examination to perm...
Source: Cardiophile MD - Category: Cardiology Authors: Tags: HBC Source Type: blogs
CONCLUSIONS: COL5A1 c.1540G>A is the first recurring variant recognized to be associated with arterial dissections and mFMD. This variant presents with a phenotype reminiscent of vascular Ehlers-Danlos syndrome. A shared haplotype among probands supports the existence of a common founder. Relatively rare COL5A1 genetic variants predicted to be deleterious by in silico analysis were identified in ≈2.7% of mFMD cases, and as they were enriched in patients with arterial dissections, may act as disease modifiers. Molecular testing for COL5A1 should be considered in patients with a phenotype overlapping with vascular E...
Source: Arteriosclerosis, Thrombosis and Vascular Biology - Category: Cardiology Authors: Tags: Arterioscler Thromb Vasc Biol Source Type: research
Ehlers-Danlos Syndrome (EDS) comprises a heterogeneous group of diseases characterized by joint hypermobility, connective tissue friability, and vascular fragility. Reliable prognostic factors predicting vascu...
Source: BMC Cardiovascular Disorders - Category: Cardiology Authors: Tags: Research article Source Type: research
This article will focus on the surgical management of patients with knee or shoulder abnormalities related to hEDS/JHS. PMID: 32904109 [PubMed - in process]
Source: Clinics in Orthopedic Surgery - Category: Orthopaedics Tags: Clin Orthop Surg Source Type: research
CONCLUSION: Many adults with Loeys-Dietz- or vascular Ehlers-Danlos syndrome may have a potential to reach more favorable physical activity levels by increasing the frequency and duration of activities. Future directions should include evaluation of effects of professional-led practical and safe physical activity sessions as well as customized multidisciplinary rehabilitation programs for these patient groups. PMID: 32915071 [PubMed - as supplied by publisher]
Source: Disability and Rehabilitation - Category: Rehabilitation Authors: Tags: Disabil Rehabil Source Type: research
Tenascins are extra cellular matrix glycoproteins largely associated with anti-adhesive effects [1]. There exist different tenascin isoforms. One of them is tenascin-X (TNX) encoded by TNXB gene [2]. TNX is localized in connective tissues, musculoskeletal, cardiac, and dermal tissue. A significant role in collagen fibrillogenesis is suggested by a TNX knock-out mice that demonstrated alterations in collagen deposition that mimic Ehlers-Danlos syndrome (EDS) [1,3,4]. EDS, characterized by skin hyperextensibility, generalized joint hypermobility, easy bruising, and atrophic scarring, is caused by autosomal dominant mutations...
Source: Neuromuscular Disorders - Category: Neurology Authors: Source Type: research
Conclusions: This study revealed the impact of the syndrome on the social and daily life of patients, and not only in a physical level, but also in a psychological and social approach. These findings allow healthcare providers to know more about this disease in order to support and give advice to patients about the changes they will have to make.
Source: International Journal of Environmental Research and Public Health - Category: Environmental Health Authors: Tags: Article Source Type: research
CONCLUSION: A wide diversity in HDCT was observed at a single center. Therefore, knowledge about the phenotype-genotype correlation in HDCT is still crucial in the diagnosis of this group of diseases, and an improvement in the screening tool will be needed. PMID: 32862725 [PubMed - as supplied by publisher]
Source: Connective Tissue Research - Category: Research Tags: Connect Tissue Res Source Type: research
Publication date: Available online 27 August 2020Source: Journal of Pediatric Surgery Case ReportsAuthor(s): Melissa Wong, Patrick J. Javid
Source: Journal of Pediatric Surgery Case Reports - Category: Surgery Source Type: research
More News: Allergy & Immunology | Ehlers-Danlos Syndrome | Skin | Study