Understanding vascular Ehlers-Danlos syndrome

Impact ◽  
2018 ◽  
Vol 2018 (3) ◽  
pp. 29-31
Author(s):  
Kenneth Richard Boheler
Keyword(s):  
Cell Model ◽  
Gene Mutations ◽  
Human Condition ◽  
Patient Specific ◽  
Specific Cell ◽  
Ehlers Danlos Syndrome ◽  
Vascular Integrity ◽  
Col3a1 Gene ◽  
Collagen Iii ◽  
Danlos Syndrome

The discovery of experimentally derived induced pluripotent stem cells (iPSCs) has fostered prospects of patient-specific cell replacement therapies, novel toxicology and drug screening assays, and informative cell models for understanding disease pathogenesis. The latter is particularly valuable to the study of human syndromes caused by gene defects where animal models are lacking or inadequately mimic the human condition. One such vascular variant is Ehlers-Danlos Syndrome (EDS), a heritable disease of connective tissues involving collagen types COL5A, COL3A, tenascin-X, and to a lesser extent COL1A, lysyl hydroxlase and ADAM metallopeptidase. Among the six major types, the vascular form of EDS (vEDS) is the most severe. It results principally from mutations in the collagen III, alpha 1 (COL3A1) gene and is thought to cause aberrant collagen fibrillogenesis. These mutations contribute to catastrophic ruptures of large arteries, strokes, pregnancy-related mortalities, and pre-mature death among young adults. The presentation of this disease is heterogeneous, even among patients with the same gene mutation, and it remains unclear why some individuals exhibit severe phenotypes while others do not. In mouse models, COL3A1 deficiency mostly produces a weak disease variant without vascular ruptures, while a spontaneous COL3A1 mutation that leads to vascular defects lacks important disease features found in humans. Currently, there are no adequate therapeutic treatments. To determine how COL3A1 mutations lead to vEDS, we propose to examine and exploit a human cell model of this disease using iPSC lines derived from fibroblasts obtained from two probands. We will correct the Col3A1 gene mutations with TALENs to ensure against phenotypic iPSC variability and determine the principal source of COL3A1 secretion from iPSC-derived vascular progeny. We will examine basic growth characteristics and functional properties of these cells as well as determine the effects of doxycycline on collagen and matrix metalloproteinase synthesis (RNA and protein), stability or activity. By establishing high quality, experimentally confirmed iPSC vascular progeny, this study should lead directly to the development of reliable human tissue models of vEDS suitable for examining the effects of COL3A1 mutations on vasculogenesis and vascular integrity as well as establish a reliable system to test for possible therapeutic (pharmacological or regenerative) interventions.

scholarly journals Vascular Ehlers-Danlos syndrome in two Polish patients: identification of two novel COL3A1 gene mutations

2019 ◽  
Author(s):  
Małgorzata Konieczyńska ◽  
Ewa Wypasek ◽  
Marek Karpiński ◽  
Monika Komar ◽  
Sofie Symoens ◽  
...  
Keyword(s):  
Gene Mutations ◽  
Ehlers Danlos Syndrome ◽  
Col3a1 Gene ◽  
Danlos Syndrome

THE CLASSIC TYPE OF EHLERS–DANLOS SYNDROME: DIFFERENTIAL DIAGNOSIS AND PECULIARITIES OF PATIENT MANAGEMENT

2021 ◽  
Vol 100 (5) ◽  
pp. 62-69
Author(s):  
А.N. Semyachkina ◽  
◽  
E.А. Nikolaeva ◽  
А.R. Zabrodina ◽  
L.P. Melikyan ◽  
...  
Keyword(s):  
Differential Diagnosis ◽  
Adult Population ◽  
Gene Mutations ◽  
Hereditary Disease ◽  
Ehlers Danlos Syndrome ◽  
Severe Pathology ◽  
Type V ◽  
Danlos Syndrome

The Classic Ehlers–Danlos syndrome (cEDS) is an autosomal dominant hereditary disease caused by type V collagen defect. The incidence of pathology is estimated at 1:20,000 of the population. The results of a long-term (15 years) follow-up of a group of patients (n=18) with cEDS, including 5 boys and 13 girls aged from 3 to 18 years, are presented. The diagnosis was made based on the presence of 2 large and 5 small international diagnostic criteria in all patients. The progreduated character of the disease is shown, which is most obvious in the dynamics of the state of the musculoskeletal system. Genetic verification of the diagnosis was performed in 6 patients; 5 probands had mutations in the COL5A1 gene, and one in the COL5A2 gene. Mutations already registered in the database were detected only in 2 children. Previously unknown substitutions were found in 4 patients. The article presents the issues of differential diagnosis of this severe pathology and touches upon the issue of continuity between medical pediatric specialists and doctors of various specialties working with the adult population.

Vascular Ehlers-Danlos syndrome presenting in the ICU as aneurysmal subarachnoid haemorrhage

2021 ◽  
Vol 14 (7) ◽  
pp. e243132
Author(s):  
Inês Pimenta ◽  
Rita Varudo ◽  
Filipa Castelao ◽  
Filipe André Gonzalez
Keyword(s):  
Subarachnoid Haemorrhage ◽  
Medical History ◽  
Type Iii Collagen ◽  
Aneurysmal Subarachnoid Haemorrhage ◽  
Ehlers Danlos Syndrome ◽  
Vascular Type ◽  
Gene Coding ◽  
Col3a1 Gene ◽  
Life Threatening ◽  
Danlos Syndrome

Vascular Ehlers-Danlos syndrome is caused by mutations of COL3A1 gene coding for type III collagen. The main clinical features involve a propensity to arterial tears leading to several life-threatening conditions and intensive care unit admission. We, herein, report the case of a 34-year-old woman presenting with an aneurysmal subarachnoid haemorrhage. Endovascular coil treatment was attempted; however, the procedure was complicated by dissection of the left iliac artery and abdominal aorta. Hospital management was marked by a series of vascular and haemorrhagic complications. These events, together with some distinctive physical features and medical history, raised the suspicion of vascular type of Ehlers-Danlos syndrome. Neurological evolution was not favourable, and the patient evolved to brain death. Genetic testing was available postmortem and identified a mutation in the COL3A1 gene. This case illustrates the importance of medical history and clinical suspicion for diagnosis, which often goes unnoticed until major complications occur.

Mutation-specific Fabry disease patient-derived cell model to evaluate the amenability to chaperone therapy

2019 ◽  
Vol 56 (8) ◽  
pp. 548-556 ◽  
Author(s):  
Malte Lenders ◽  
Franciska Stappers ◽  
Christoph Niemietz ◽  
Boris Schmitz ◽  
Michel Boutin ◽  
...  
Keyword(s):  
Fabry Disease ◽  
Cell Model ◽  
White Blood Cells ◽  
Disease Patient ◽  
Patient Specific ◽  
Specific Cell ◽  
Missense Mutations ◽  
Activity Measurements

BackgroundPatients with Fabry disease (FD) and amenable mutations can be treated with the chaperone migalastat to restore endogenous α-galactosidase A (AGAL) activity. However, certain amenable mutations do not respond biochemically in vivo as expected. Here, we aimed to establish a patient-specific and mutation-specific cell model to evaluate the amenability to chaperone therapy in FD.MethodsSince current tests to determine amenability are limited to heterologous mutation expression in HEK293T cells with endogenous AGAL activity, we generated CRISPR/Cas9-mediated AGAL-deficient HEK293T cells as a basis for mutant overexpression. Furthermore, primary urinary cells from patients were isolated and immortalised as a patient-specific cell model system to evaluate the amenability to chaperone therapy.ResultsUnder treatment (>13 months), carriers of p.N215S (n=6) showed a significant reduction of plasma lyso-Gb3 (p<0.05). Lyso-Gb3 levels in carriers of p.L294S increased (p<0.05) and two patients developed severe albuminuria. Both missense mutations were amenable in wild-type HEK293T cells (p<0.05), but presented different responses in CRISPR/Cas9-mediated AGAL knockouts and immortalised urinary cells. Chaperone incubation resulted in increased AGAL activity (p<0.0001) and intracellular globotriaosylceramide (Gb3) reduction (p<0.05) in immortalised p.N215S cells but not in p.L294S and IVS2+1 G>A cells.ConclusionWe conclude that repeated AGAL activity measurements in patients’ white blood cells are mandatory to assess the in vivo amenability to migalastat. Plasma lyso-Gb3 might be an appropriate tool to measure the biochemical response to migalastat. Patients with low AGAL activities and increasing lyso-Gb3 levels despite in vitro amenability might not benefit sufficiently from chaperone treatment.

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 The type of variants at the COL3A1 gene associates with the phenotype and severity of vascular Ehlers–Danlos syndrome

2015 ◽  
Vol 23 (12) ◽  
pp. 1657-1664 ◽  
Author(s):  
Michael Frank ◽  
Juliette Albuisson ◽  
Brigitte Ranque ◽  
Lisa Golmard ◽  
Jean-Michael Mazzella ◽  
...  
Keyword(s):  
Ehlers Danlos Syndrome ◽  
Col3a1 Gene ◽  
Danlos Syndrome

Single base mutation that substitutes glutamic acid for glycine 1021 in the COL3A1 gene and causes Ehlers-Danlos syndrome type IV

1993 ◽  
Vol 46 (3) ◽  
pp. 278-283 ◽  
Author(s):  
Paolo Narcisi ◽  
Yuli Wu ◽  
Gerard Tromp ◽  
James J Earley ◽  
Allan J. Richards ◽  
...  
Keyword(s):  
Glutamic Acid ◽  
Syndrome Type ◽  
Ehlers Danlos Syndrome ◽  
Single Base ◽  
Type Iv ◽  
Col3a1 Gene ◽  
Danlos Syndrome
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