ehlers danlos extracellular matrix
195796092
Novel defects in collagen XII and VI expand the mixed myopathy/Ehlers Danlos syndrome spectrum and lead to variant specific alterations in the extracellular matrix
Purpose To date, heterozygous or homozygous COL12A1 variants have been reported in 13 patients presenting with a clinical phenotype overlapping with collagen VI related myopathies and Ehlers Danlos syndrome (EDS) The small number of reported patients limits thorough investigation of this newly identified syndrome, currently coined as myopathic EDS. Methods DNA from 78 genetically unresolved patients fulfilling the clinical criteria for myopathic EDS was sequenced using a next generation panel of COL12A1 COL6A1 COL6A2 and COL6A3 Results Among this cohort, we identified four pathogenic heterozygous in frame exon skipping defects in COL12A1 clustering to the thrombospondin N terminal region and the adjacent collagenous domain (D52, D53, D54, and D56 respectively) one heterozygous COL12A1 arginine to cysteine substitution of unclear significance (p.(Arg1863Cys) and compound heterozygous pathogenic COL6A1 variants (c.[98 6G>A][301C>T] in one proband. Variant specific intracellular accumulation of collagen XII chains, extracellular overmodification of the long isoform and near absence of the short isoform of collagen XII, and extracellular decrease of decorin and tenascin X were observed for the COL12A1 variants. In contrast, the COL6A1 variants abolished collagen VI and V deposition and increased tenascin X levels. Conclusion Our data further support the significant clinical overlap between myopathic EDS and collagen VI related myopathies, and emphasize the variant specific consequences of collagen XII defects.
Genetics in Medicine
Sarah Delbaere Tibbe Dhooge Delfien Syx Florence Petit Nathalie Goemans Anne Destree Olivier M Vanakker Riet De Rycke Sofie Symoens Fransiska Malfait
199075477
Heterozygous defects in collagen XII cause myopathic Ehlers Danlos syndrome and lead to variant specific alterations in the extracellular matrix
Sarah Delbaere Tibbe Dhooge Delfien Syx Florence Petit Nathalie Goemans Anne Destree Olivier M Vanakker Riet de Rycke Sofie Symoens Fransiska Malfait
4663936
Bi allelic Alterations in AEBP1 Lead to Defective Collagen Assembly and Connective Tissue Structure Resulting in a Variant of Ehlers Danlos Syndrome.
AEBP1 encodes the aortic carboxypeptidase like protein (ACLP) that associates with collagens in the extracellular matrix (ECM) and has several roles in development, tissue repair, and fibrosis. ACLP is expressed in bone, the vasculature, and dermal tissues and is involved in fibroblast proliferation and mesenchymal stem cell differentiation into collagen producing cells. Aebp1 mice have abnormal, delayed wound repair correlating with defects in fibroblast proliferation. In this study, we describe four individuals from three unrelated families that presented with a unique constellation of clinical findings including joint laxity, redundant and hyperextensible skin, poor wound healing with abnormal scarring, osteoporosis, and other features reminiscent of Ehlers Danlos syndrome (EDS) Analysis of skin biopsies revealed decreased dermal collagen with abnormal collagen fibrils that were ragged in appearance. Exome sequencing revealed compound heterozygous variants in AEBP1 (c.1470delC [p.Asn490_Met495delins(40) and c.1743C>A [p.Cys581* in the first individual, a homozygous variant (c.1320_1326del [p.Arg440Serfs*3] in the second individual, and a homozygous splice site variant (c.1630+1G>A) in two siblings from the third family. We show that ACLP enhances collagen polymerization and binds to several fibrillar collagens via its discoidin domain. These studies support the conclusion that bi allelic pathogenic variants in AEBP1 are the cause of this autosomal recessive EDS subtype.
American journal of human genetics
Patrick R Blackburn Zhi Xu Kathleen E Tumelty Rose W Zhao William J Monis Kimberly G Harris Jennifer M Gass Margot A Cousin Nicole J Boczek Mario V Mitkov Mark Aaron Cappel Clair A Francomano Joseph E Parisi Eric W Klee Eissa Ali Faqeih Fowzan S Alkuraya Matthew D Layne Nazli B McDonnell Paldeep S Atwal
73446165
Expanding the Clinical and Mutational Spectrum of Recessive AEBP1 Related Classical Like Ehlers Danlos Syndrome
Ehlers Danlos syndrome (EDS) comprises clinically heterogeneous connective tissue disorders with diverse molecular etiologies. The 2017 International Classification for EDS recognized 13 distinct subtypes caused by pathogenic variants in 19 genes mainly encoding fibrillar collagens and collagen modifying or processing proteins. Recently, a new EDS subtype, i.e. classical like EDS type 2, was defined after the identification, in six patients with clinical findings reminiscent of EDS, of recessive alterations in AEBP1, which encodes the aortic carboxypeptidase like protein associating with collagens in the extracellular matrix. Herein, we report on a 53 year old patient, born from healthy second cousins, who fitted the diagnostic criteria for classical EDS (cEDS) for the presence of hyperextensible skin with multiple atrophic scars, generalized joint hypermobility, and other minor criteria. Molecular analyses of cEDS genes did not identify any causal variant. Therefore, AEBP1 sequencing was performed that revealed homozygosity for the rare c.1925T>C p.(Leu642Pro) variant classified as likely pathogenetic (class 4) according to the American College of Medical Genetics and Genomics (ACMG) guidelines. The comparison of the patient's features with those of the other patients reported up to now and the identification of the first missense variant likely associated with the condition offer future perspectives for EDS nosology and research in this field.
Genes
Marco Ritelli Valeria Cinquina M Venturini Letizia Pezzaioli Anna Maria Formenti Nicola Chiarelli Marina Colombi
13705584
Vascular aspects of the Ehlers Danlos Syndromes.
The Ehlers Danlos Syndromes comprise a heterogeneous group of rare monogenic conditions that are characterized by joint hypermobility, skin and vascular fragility and generalized connective tissue friability. The latest classification recognizes 13 clinical subtypes, with mutations identified in 19 different genes. Besides defects in fibrillar collagens (collagen types I, III and V) their modifying enzymes (ADAMTS 2, lysylhydroxylase 1 (LH1) and molecules involved in collagen folding (FKBP22) defects have recently been identified in other constituents of the extracellular matrix (e.g. Tenascin X, collagen type XII) enzymes involved in glycosaminoglycan biosynthesis (b4GalT7 and b3GalT6) dermatan 4 O sulfotransferase 1 (D4ST1) dermatan sulfate epimerase (DSE) (putative) transcription factors (ZNF469, PRDM5) components of the complement pathway (C1r, C1s) and an intracellular Zinc transporter (ZIP13) Easy bruising is, to a variable degree, present in all subtypes of EDS. A variable bleeding tendency, manifesting e.g. as gum bleeding, menometrorraghia, postnatal or peri operative hemorrhage is observed in many EDS patients of varying EDS subtypes. Life threatening arterial aneurysms, dissections and ruptures of medium sized and large arteries are a hallmark of the vascular subtype of EDS, caused by a molecular defect in collagen type III, an important constituent of blood vessel walls and hollow organs. They may however also occur in other EDS subtypes, especially in classical EDS, caused by defects in type V collagen or, rarely, type I collagen, and in kyphoscoliotic EDS, caused by defects in LH1 or FKBP22. These manifestations of vascular fragility and bleeding are usually attributed to fragility of the blood vessel walls and the perivascular connective tissues, but the molecular pathomechanisms underlying these complications are poorly studied. This review summarizes current knowledge on manifestations of vascular fragility in the different EDS subtypes.
Matrix biology journal of the International Society for Matrix Biology
Fransiska Malfait
195871918
Transcriptome Profiling of Primary Skin Fibroblasts Reveal Distinct Molecular Features Between PLOD1 and FKBP14 Kyphoscoliotic Ehlers 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.
Genes
Pei Jin Lim Uschi Lindert Lennart Opitz Ingrid Hausser Marianne Rohrbach Cecilia Giunta
71148161
Understanding the basis of Ehlers Danlos syndrome in the era of the next generation sequencing
Ehlers Danlos syndrome (EDS) is a clinically and genetically heterogeneous group of heritable connective tissue disorders (HCTDs) defined by joint laxity, skin alterations, and joint hypermobility. The latest EDS classification recognized 13 subtypes in which the clinical and genetic phenotypes are often overlapping, making the diagnosis rather difficult and strengthening the importance of the molecular diagnostic confirmation. New genetic techniques such as next generation sequencing (NGS) gave the opportunity to identify the genetic bases of unresolved EDS types and support clinical counseling. To date, the molecular defects have been identified in 19 genes, mainly in those encoding collagen, its modifying enzymes or other constituents of the extracellular matrix (ECM) In this review we summarize the contribution of NGS technologies to the current knowledge of the genetic background in different EDS subtypes.
Archives of Dermatological Research
Francesca Cortini Chiara Villa Barbara Marinelli Romina Combi Angela Cecilia Pesatori Alessandra Bassotti
198999641
Compound heterozygosity for TNXB genetic variants in a mixed breed dog with Ehlers Danlos syndrome.
The Ehlers Danlos syndromes (EDSs) are a heterogeneous group of inherited connective tissue disorders characterized by skin hyperextensibility, joint hypermobility and tissue fragility. Inherited disorders similar to human EDS have been reported in different mammalian species. In the present study, we investigated a female mixed breed dog with clinical signs of EDS. Whole genome sequencing of the affected dog revealed two missense variants in the TNXB gene, encoding the extracellular matrix protein tenascin XB. In humans, TNXB genetic variants cause classical like EDS or the milder hypermobile EDS. The affected dog was heterozygous at both identified variants. Each variant allele was transmitted from one of the case's parents, consistent with compound heterozygosity. Although one of the variant alleles, XM_003431680.3:c.2012G>A, p.(Ser671Asn) was private to the family of the affected dog and absent from whole genome sequencing data of 599 control dogs, the second variant allele, XM_003431680.3:c.2900G>A, p.(Gly967Asp) is present at a low frequency in the Chihuahua and Poodle population. Given that TNXB is a functional candidate gene for EDS, we suggest that compound heterozygosity for the identified TNXB variants may have caused the EDS like phenotype in the affected dog. Chihuahuas and Poodles should be monitored for EDS cases, which might confirm the hypothesized pathogenic effect of the segregating TNXB variant.
Animal genetics
Anina Bauer Michela De Lucia Fabienne Leuthard Vidhya Jagannathan Tosso Leeb
64366332
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. cEDS patients suffer from skin hyperextensibility, abnormal wound healing/atrophic scars, and joint hypermobility. 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. Transcriptome profiling revealed significant changes in the expression levels of different extracellular matrix (ECM) related genes, such as SPP1, POSTN, EDIL3, IGFBP2, and C3, which encode both matricellular and soluble proteins that are mainly involved in cell proliferation and migration, and cutaneous wound healing. 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. Microarray analysis also indicated the decreased expression of DNAJB7, VIPAS39, CCPG1, ATG10, SVIP, which encode molecular chaperones facilitating protein folding, enzymes regulating post Golgi COLLs processing, and proteins acting as cargo receptors required for endoplasmic reticulum (ER) proteostasis and implicated in the autophagy process. Patients' cells also showed altered mRNA levels of many cell cycle regulating genes including CCNE2, KIF4A, MKI67, DTL, and DDIAS. Protein studies showed that aberrant COLLV expression causes the disassembly of itself and many structural ECM constituents including COLLI, COLLIII, fibronectin, and fibrillins. 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.
PloS one
Nicola Chiarelli Giulia Carini Nicoletta Zoppi Marco Ritelli Marina Colombi
173992921
Use of Cluster Analysis to Delineate Symptom Profiles in Ehlers Danlos Syndrome Patient Population.
CONTEXT The Ehlers Danlos Syndromes (EDSs) are a set of rare heritable disorders of connective tissue, characterized by defects in the structure and synthesis of extracellular matrix elements that lead to a myriad of problems including joint hypermobility and skin abnormalities. Because EDS affects multiple organ systems, defining clear boundaries and recognizing overlapping clinical features shared by disease phenotypes is challenging. OBJECTIVES The objective of this study was to seek evidence of phenotypic subgroups of patients with distinctive symptom profiles and describe these resulting subgroups. METHODS Data were extracted from a repository assembled 2001 2013 by the National Institute on Aging Intramural Research Program. Agglomerative hierarchical clustering was used to form distinct subgroups of patients with respect to the domains of pain, physical and mental fatigue, daytime sleepiness, and nighttime sleep. Domains were selected based on literature review, clinician expertise, and guidance from patient advisors. RESULTS One hundred seventy five patients met all inclusion criteria. Three subgroups were identified. The Pain Dominant subgroup (39 patients) had the highest mean pain values, but lowest mean values of other symptoms. The High Symptom Burden subgroup (71 patients) had high mean values in all domains. The Mental Fatigue subgroup (65 patients) had a high mean value for mental fatigue and daytime sleepiness, but a lower mean value for pain. CONCLUSION The subgroups aligned with clinical observation of the heterogeneous nature of EDS, with overlapping symptoms between subtypes and a wide divergence in degree of symptoms within subtypes. This exploratory study helps characterize the various phenotypes and comorbidities of patients with EDS.
Journal of pain and symptom management
Jane R Schubart Eric W Schaefer Alan J Hakim Clair A Francomano Rebecca Bascom