A hereditary connective tissue disorder caused by pathogenic variants in the COL5A1 gene, which encodes the alpha-1 chain of type V collagen. This form accounts for approximately 50% of classic Ehlers-Danlos syndrome cases and is characterized by skin hyperextensibility, fragile and soft skin, delayed wound healing with formation of atrophic scars, easy bruising, and generalized joint hypermobility. The disease follows autosomal dominant inheritance with variable expressivity.
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name: Ehlers-Danlos Syndrome, COL5A1-related
creation_date: '2025-12-04T16:57:31Z'
updated_date: '2026-04-03T20:00:00Z'
description: >-
A hereditary connective tissue disorder caused by pathogenic variants in the COL5A1 gene,
which encodes the alpha-1 chain of type V collagen. This form accounts for approximately
50% of classic Ehlers-Danlos syndrome cases and is characterized by skin hyperextensibility,
fragile and soft skin, delayed wound healing with formation of atrophic scars, easy
bruising, and generalized joint hypermobility. The disease follows autosomal dominant
inheritance with variable expressivity.
category: Genetic
parents:
- Ehlers-Danlos Syndrome
prevalence:
- population: Global
percentage: 0.002-0.01
evidence:
- reference: PMID:20847697
reference_title: "Clinical and genetic aspects of Ehlers-Danlos syndrome, classic type."
supports: PARTIAL
snippet: 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.
explanation: This reference indicates that COL5A1-related EDS is a subset of classic EDS, making up about 50% of classic EDS cases. However, it does not provide specific global prevalence rates of COL5A1-related EDS.
progression:
- phase: Onset
age_range: Birth-20
evidence:
- reference: PMID:20847697
reference_title: "Clinical and genetic aspects of Ehlers-Danlos syndrome, classic type."
supports: PARTIAL
snippet: 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.
explanation: While the COL5A1-related Ehlers-Danlos Syndrome (classic type) is described as a heritable connective tissue disorder with certain clinical features observable from birth, the literature does not specifically detail the age range for the onset of symptoms as 'Birth-20'.
pathophysiology:
- name: Collagen Type V Abnormalities
description: Mutations in the COL5A1 gene lead to defective collagen type V synthesis and assembly.
biological_processes:
- preferred_term: collagen fibril organization
term:
id: GO:0030199
label: collagen fibril organization
- preferred_term: collagen biosynthetic process
term:
id: GO:0032964
label: collagen biosynthetic process
evidence:
- reference: PMID:9042913
reference_title: "Mutations in the COL5A1 gene are causal in the Ehlers-Danlos syndromes I and II."
supports: SUPPORT
snippet: The mutation causes the substitution of the most 5' cysteine residue by a serine within a highly conserved sequence of the pro(alpha)1(V) C-propeptide domain and causes reduction of collagen V by preventing incorporation of the mutant pro(alpha)1(V) chains in the collagen V trimers.
explanation: This reference describes how mutations in COL5A1 lead to defective synthesis and assembly of collagen type V, supporting the given statement.
downstream:
- target: Connective Tissue Fragility
description: Reduced type V collagen impairs fibril nucleation and ECM tensile strength.
- name: Connective Tissue Fragility
description: Abnormal collagen type V leads to weakened connective tissues throughout the body.
cell_types:
- preferred_term: fibroblast
term:
id: CL:0000057
label: fibroblast
- preferred_term: dermal fibroblast
term:
id: CL:0002620
label: skin fibroblast
biological_processes:
- preferred_term: extracellular matrix organization
term:
id: GO:0030198
label: extracellular matrix organization
cellular_components:
- preferred_term: extracellular matrix
term:
id: GO:0031012
label: extracellular matrix
evidence:
- reference: PMID:20847697
reference_title: "Clinical and genetic aspects of Ehlers-Danlos syndrome, classic type."
supports: SUPPORT
snippet: 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.
explanation: The literature indicates that mutations in the COL5A1 gene lead to abnormalities in collagen type V, resulting in weakened connective tissues.
- reference: PMID:15095409
reference_title: "Reduced type I collagen utilization: a pathogenic mechanism in COL5A1 haplo-insufficient Ehlers-Danlos syndrome."
supports: SUPPORT
snippet: EDS cells with COL5A1 haplo-insufficiency deposited less than one-half of hydroxyproline as collagen compared to control fibroblasts. ... a reduction of type V collagen, in the EDS derived cells, was associated with the assembly of significantly fewer fibrils compared to control and OI cells.
explanation: This study demonstrates that reduced type V collagen results in weaker connective tissue due to a significant decrease in collagen fibril assembly.
- reference: PMID:12836217
reference_title: "[The Ehlers-Danlos syndrome: the extracellular matrix scaffold in question]."
supports: SUPPORT
snippet: The classical form of the syndrome, which will be principally discussed in this review, can be due to mutations on collagen V, a fibrillar collagen present in small amounts in affected tissues.
explanation: The literature describes the role of collagen V and its mutations in causing connective tissue fragility, therefore supporting the statement.
downstream:
- target: Tissue Injury and Dysfunction
description: Collagen-poor matrices fail under repetitive motion and minor trauma.
- target: Joint Hypermobility
description: Ligamentous laxity from weak collagen fibrils permits excessive joint excursion.
- target: Skin Hyperextensibility
description: Dermal matrix weakness allows abnormal skin stretchability.
- target: Easy Bruising
description: Fragile perivascular connective tissue increases capillary vulnerability.
- target: Mitral Valve Prolapse
description: Valve leaflet connective tissue laxity predisposes to prolapse.
- target: Myopia
description: Scleral connective tissue weakness can increase axial elongation.
- name: Tissue Injury and Dysfunction
description: Fragile tissues are prone to damage, leading to manifestations like joint dislocations, skin hyperextensibility, and poor wound healing. Impaired wound healing involves altered mechanosensitive integrin signaling and defective re-epithelialization.
cell_types:
- preferred_term: keratinocyte
term:
id: CL:0000312
label: keratinocyte
locations:
- preferred_term: skin of body
term:
id: UBERON:0002097
label: skin of body
- preferred_term: tendon
term:
id: UBERON:0000043
label: tendon
- preferred_term: corneal stroma
term:
id: UBERON:0001777
label: substantia propria of cornea
biological_processes:
- preferred_term: wound healing
term:
id: GO:0042060
label: wound healing
- preferred_term: signal transduction
term:
id: GO:0007165
label: signal transduction
- preferred_term: integrin-mediated signaling pathway
term:
id: GO:0007229
label: integrin-mediated signaling pathway
cellular_components:
- preferred_term: pericellular matrix
term:
id: GO:0031012
label: extracellular matrix
evidence:
- reference: PMID:19370768
reference_title: "Molecular mechanisms of classical Ehlers-Danlos syndrome (EDS)."
supports: PARTIAL
snippet: Classical Ehlers-Danlos syndrome (EDS) is a heritable disorder characterized by joint hypermobility, skin hyperextensibility, and abnormal wound healing.
explanation: Supports core cEDS tissue fragility features, but only partially supports the full mechanistic descriptor.
- reference: PMID:19592142
reference_title: "Bleeding in the heritable connective tissue disorders: mechanisms, diagnosis and treatment."
supports: PARTIAL
snippet: The bleeding tendency is most prominent in the Ehlers-Danlos syndrome (EDS), a heterogeneous group of HDCT sharing clinical manifestations of fragility in skin, ligaments, blood vessels and internal organs.
explanation: Supports generalized tissue fragility in EDS, but only partially supports this COL5A1-specific mechanism statement.
- reference: PMID:20697718
reference_title: "Ehlers-Danlos syndrome and neurological features: a review."
supports: PARTIAL
snippet: Ehlers-Danlos Syndrome is a term that comprises a variety of inherited connective tissue disorders characterized primarily by skin hyperextensibility, joints hypermobility and excessive dislocations, easy bruisability, generalized fragility.
explanation: Supports broad EDS clinical fragility features, but not the full mechanistic details in this descriptor.
- reference: PMID:19055167
reference_title: "A \"hyperextensive\" review of Ehlers-Danlos syndrome."
supports: PARTIAL
snippet: Ehlers-Danlos syndrome (EDS) is a heterogeneous group of connective tissue disorders characterized by hyperextensibility, delayed wound healing, joint hypermobility, thin skin, easy bruising, tissue fragility, 'cigarette-paper' scarring over bony prominences.
explanation: Supports core cEDS phenotype features, but only partially supports this detailed pathophysiology statement.
downstream:
- target: Recurrent Joint Dislocations
description: Repetitive instability episodes result in frequent subluxations and dislocations.
- target: Chronic Joint Pain
description: Ongoing mechanical injury and microinstability lead to chronic pain.
- target: Delayed Wound Healing
description: Defective collagen remodeling slows re-epithelialization and scar strengthening.
- target: Atrophic Scarring
description: Poor collagen deposition produces thin widened scars.
- target: Molluscoid Pseudotumors
description: Recurrent focal trauma and disordered repair produce fibrotic nodular lesions.
- target: Gastroesophageal Reflux
description: Connective tissue laxity at the gastroesophageal junction can impair sphincter competence.
phenotypes:
- category: Musculoskeletal
name: Joint Hypermobility
description: Abnormally increased range of motion in multiple joints due to lax connective tissue.
frequency: VERY_FREQUENT
diagnostic: true
sequelae:
- target: Recurrent Joint Dislocations
description: Joint hypermobility predisposes to repeated episodes of joint displacement.
- target: Chronic Joint Pain
description: Persistent joint pain resulting from joint instability and repeated subluxations.
evidence:
- reference: PMID:34807421
reference_title: "Ehlers-Danlos Syndromes, Joint Hypermobility and Hypermobility Spectrum Disorders."
supports: SUPPORT
snippet: Currently, musculoskeletal manifestations related to joint hypermobility are perceived as the most prevalent determinants of the quality of life of affected individuals.
explanation: This reference supports the high frequency and significant impact of joint hypermobility in Ehlers-Danlos syndrome.
- reference: PMID:19370768
reference_title: "Molecular mechanisms of classical Ehlers-Danlos syndrome (EDS)."
supports: SUPPORT
snippet: Classical Ehlers-Danlos syndrome (EDS) is a heritable disorder characterized by joint hypermobility, skin hyperextensibility, and abnormal wound healing.
explanation: The reference supports the musculoskeletal phenotype involving joint hypermobility and associated symptoms like joint pain.
- reference: PMID:35964930
reference_title: "Phenotype of COL3A1/COL5A2 deletion patients."
supports: PARTIAL
snippet: Classical (cEDS) and vascular type (vEDS) are the most prevalent subtypes and are caused by heterozygous pathogenic variants in COL5A1, COL5A2, COL1A1 or, respectively, in COL3A1.
explanation: Supports COL5A1 association with cEDS, but only indirectly supports the specific joint hypermobility claim.
- reference: PMID:10906878
reference_title: "Orthopaedic manifestations of Ehlers-Danlos syndrome."
supports: PARTIAL
snippet: Thirty patients with Type III Ehlers-Danlos syndrome reported joint pain more frequently than did patients with Types I, II, or IV.
explanation: Supports joint pain burden in an EDS subgroup, but only partially supports this COL5A1-specific joint hypermobility descriptor.
phenotype_term:
preferred_term: Joint Hypermobility
term:
id: HP:0001382
label: Joint hypermobility
- category: Dermatologic
name: Skin Hyperextensibility
description: Skin that can be stretched beyond the normal range and returns to its original position when released.
frequency: VERY_FREQUENT
diagnostic: true
evidence:
- reference: PMID:20847697
reference_title: "Clinical and genetic aspects of Ehlers-Danlos syndrome, classic type."
supports: SUPPORT
snippet: Classic Ehlers-Danlos syndrome is a heritable connective tissue disorder characterized by skin hyperextensibility, fragile and soft skin...
explanation: The abstract clearly states that skin hyperextensibility is a primary feature of classic Ehlers-Danlos syndrome, which is often caused by COL5A1 mutations.
- reference: PMID:36764582
reference_title: "Dermatologic manifestations and diagnostic assessments of the Ehlers-Danlos syndromes: A clinical review."
supports: SUPPORT
snippet: A high prevalence of skin hyperextensibility, bruising, and soft skin were noted.
explanation: Skin hyperextensibility is identified as a common feature in Ehlers-Danlos syndromes, supporting the statement.
- reference: PMID:37594181
reference_title: "Precision medicine using whole genome sequencing in a cat identifies a novel COL5A1 variant for classical Ehlers-Danlos syndrome."
supports: NO_EVIDENCE
snippet: The classic tragic facial expression was observed as well as chronic pruritus and mild hyperesthesia.
explanation: Snippet does not directly provide evidence for skin hyperextensibility.
- category: Dermatologic
name: Atrophic Scarring
description: Formation of thin, widened scars with a papyraceous or cigarette-paper appearance, typically over bony prominences.
frequency: VERY_FREQUENT
diagnostic: true
evidence:
- reference: PMID:20847697
reference_title: "Clinical and genetic aspects of Ehlers-Danlos syndrome, classic type."
supports: SUPPORT
snippet: 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.
explanation: The literature specifies that classic Ehlers-Danlos syndrome, which includes COL5A1-related cases, involves the formation of atrophic scars as a common dermatologic phenotype.
- category: Dermatologic
name: Easy Bruising
description: Increased susceptibility to bruising from minor trauma due to fragile blood vessels and connective tissue.
frequency: FREQUENT
evidence:
- reference: PMID:20847697
reference_title: "Clinical and genetic aspects of Ehlers-Danlos syndrome, classic type."
supports: SUPPORT
snippet: Classic Ehlers-Danlos syndrome is a heritable connective tissue disorder characterized by ... easy bruising.
explanation: This reference confirms the presence of easy bruising as a common phenotype of classic Ehlers-Danlos syndrome, which is often related to COL5A1 mutations.
- reference: PMID:36764582
reference_title: "Dermatologic manifestations and diagnostic assessments of the Ehlers-Danlos syndromes: A clinical review."
supports: SUPPORT
snippet: The Ehlers-Danlos syndromes (EDSs) comprise a group of connective tissue disorders that manifest with... easy bruising...
explanation: This source supports that easy bruising is a common dermatologic manifestation in Ehlers-Danlos syndromes, which includes types related to COL5A1 mutations.
- reference: PMID:15566352
reference_title: "Bleeding and bruising in patients with Ehlers-Danlos syndrome and other collagen vascular disorders."
supports: SUPPORT
snippet: Easy bruising is, to a variable degree, present in all subtypes of EDS...
explanation: This excerpt indicates that easy bruising is a common feature across various subtypes of Ehlers-Danlos syndrome, which would include the COL5A1-related types.
- category: Cardiovascular
name: Mitral Valve Prolapse
description: Abnormal bulging of the mitral valve leaflets into the left atrium during systole due to connective tissue laxity.
frequency: OCCASIONAL
evidence:
- reference: PMID:21193204
reference_title: "Cross-sectional and longitudinal assessment of aortic root dilation and valvular anomalies in hypermobile and classic Ehlers-Danlos syndrome."
supports: PARTIAL
snippet: Fifteen of the 252 patients (6.0%) had mitral valve prolapse (MVP), although only one patient (0.4%) had MVP that was mild to moderate.
explanation: The literature shows an occasional incidence of mitral valve prolapse in Ehlers-Danlos Syndrome, and while the exact subtype related to COL5A1 is not specified, it partially supports the statement.
- reference: PMID:34776077
reference_title: "The Heart Muscle and Valve Involvement in Marfan Syndrome, Loeys-Dietz Syndromes, and Collagenopathies."
supports: SUPPORT
snippet: The EDS are currently classified into thirteen subtypes. There is substantial symptoms overlap between the EDS subtypes, and they are associated with an increased incidence of cardiovascular abnormalities, such as mitral valve prolapse and aortic dissection.
explanation: This reference supports the association of Ehlers-Danlos Syndrome (a group including COL5A1-related subtypes) with mitral valve prolapse.
phenotype_term:
preferred_term: Mitral Valve Prolapse
term:
id: HP:0001634
label: Mitral valve prolapse
- category: Gastrointestinal
name: Gastroesophageal Reflux
description: Backflow of stomach contents into the esophagus, possibly related to laxity of the lower esophageal sphincter.
frequency: OCCASIONAL
evidence:
- reference: PMID:26376608
reference_title: "Ehlers Danlos syndrome and gastrointestinal manifestations: a 20-year experience at Mayo Clinic."
supports: PARTIAL
snippet: 'Commonest GI symptoms were: abdominal pain (56.1%), nausea (42.3%), constipation (38.6%), heartburn (37.6%), and irritable bowel syndrome-like symptoms (27.5%)... Among 37.8% of the 378 patients who underwent esophagogastroduodenoscopy, the commonest abnormalities were gastritis, hiatal hernia and reflux esophagitis.'
explanation: The study indicates that reflux esophagitis, which is related to gastroesophageal reflux, is one of the common abnormalities observed in EDS patients. However, it does not explicitly distinguish the frequency of this phenotype for COL5A1-related EDS specifically.
phenotype_term:
preferred_term: Gastroesophageal Reflux
term:
id: HP:0002020
label: Gastroesophageal reflux
- category: Dermatologic
name: Molluscoid Pseudotumors
description: Fleshy, scar-associated lesions that develop over pressure points and areas of repeated trauma.
frequency: OCCASIONAL
evidence:
- reference: PMID:27905128
reference_title: "Ehlers-Danlos syndrome related to FKBP14 mutations: detailed cutaneous phenotype."
supports: SUPPORT
snippet: Molluscoid pseudotumours are a characteristic finding in patients with the classic ED variant, but are rarely reported in other variants.
explanation: The literature confirms that molluscoid pseudotumors are characteristic of the classic variant of Ehlers-Danlos Syndrome, which can be COL5A1-related. This supports the statement that these dermatologic features can occur occasionally in such cases.
phenotype_term:
preferred_term: Molluscoid Pseudotumors
term:
id: HP:0000993
label: Molluscoid pseudotumors
- category: Ocular
name: Myopia
description: Nearsightedness, a refractive error where distant objects appear blurred.
frequency: OCCASIONAL
evidence:
- reference: PMID:36237549
reference_title: "Ehlers-Danlos syndromes and their manifestations in the visual system."
supports: PARTIAL
snippet: In addition to these commonly recognized phenotypes, recent studies have notably highlighted variable ophthalmic features in EDS.
explanation: The study mentions variable ophthalmic features in EDS but does not specifically mention myopia as an occasional feature related to COL5A1.
- reference: PMID:30246406
reference_title: "A frameshift variant in the COL5A1 gene in a cat with Ehlers-Danlos syndrome."
supports: NO_EVIDENCE
snippet: The affected cat showed multiple recurrent skin tears, hyperextensibility of the skin and joint abnormalities.
explanation: The study on a cat with EDS caused by a COL5A1 mutation does not mention myopia.
phenotype_term:
preferred_term: Myopia
term:
id: HP:0000545
label: Myopia
- category: Musculoskeletal
name: Recurrent Joint Dislocations
description: Repeated episodes of joints becoming displaced from their normal positions.
frequency: FREQUENT
evidence:
- reference: PMID:20697718
reference_title: "Ehlers-Danlos syndrome and neurological features: a review."
supports: SUPPORT
snippet: Ehlers-Danlos Syndrome is a term that comprises a variety of inherited connective tissue disorders characterized primarily by skin hyperextensibility, joints hypermobility and excessive dislocations, easy bruisability, generalized fragility.
explanation: The literature supports excessive dislocations as a characteristic feature of Ehlers-Danlos Syndrome.
phenotype_term:
preferred_term: Recurrent Joint Dislocations
term:
id: HP:0001373
label: Joint dislocation
- category: Musculoskeletal
name: Chronic Joint Pain
description: Persistent pain in multiple joints resulting from joint instability, subluxations, and degenerative changes.
frequency: FREQUENT
evidence:
- reference: PMID:10906878
reference_title: "Orthopaedic manifestations of Ehlers-Danlos syndrome."
supports: PARTIAL
snippet: Thirty patients with Type III Ehlers-Danlos syndrome reported joint pain more frequently than did patients with Types I, II, or IV.
explanation: Supports joint pain in an EDS subgroup, but only partially supports this COL5A1-related phenotype frequency claim.
phenotype_term:
preferred_term: Chronic Joint Pain
term:
id: HP:0002829
label: Arthralgia
- category: Dermatologic
name: Delayed Wound Healing
description: Prolonged time for wounds to heal with impaired re-epithelialization and abnormal granulation tissue formation.
frequency: VERY_FREQUENT
diagnostic: true
evidence:
- reference: PMID:20847697
reference_title: "Clinical and genetic aspects of Ehlers-Danlos syndrome, classic type."
supports: SUPPORT
snippet: 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.
explanation: Delayed wound healing is a core feature of classic EDS due to defective collagen V.
phenotype_term:
preferred_term: Delayed Wound Healing
term:
id: HP:0001030
label: Fragile skin
biochemical:
- name: Collagen Type V
presence: Decreased or Abnormal
evidence:
- reference: PMID:21697718
reference_title: "Type V collagen genotype and exercise-related phenotype relationships: a novel hypothesis."
supports: PARTIAL
snippet: We have shown that a variant within COL5A1, which encodes a subunit of type V collagen, is associated with injury and performance phenotypes. Although seemingly unrelated, these phenotypes are associated directly or indirectly with the mechanical properties of musculoskeletal soft tissue.
explanation: Supports COL5A1 variant functional relevance, but only indirectly supports this biochemical presence claim.
- reference: PMID:33189937
reference_title: "Low penetrance COL5A1 variants in a young patient with intracranial aneurysm and very mild signs of Ehlers-Danlos syndrome."
supports: SUPPORT
snippet: Functional assays demonstrated a significant decrease of collagen alpha1(V) chain expression in both heterozygous parents compared to control cells, and an additive effect of these two variants in the proband.
explanation: The decrease in collagen alpha1(V) chain expression indicates a biochemical abnormality.
- reference: PMID:20979576
reference_title: "Identification of binding partners interacting with the α1-N-propeptide of type V collagen."
supports: PARTIAL
snippet: Mutations in COL5A1 or COL5A2, encoding respectively the alpha1(V)- and alpha2(V)-collagen chain, cause classic EDS (Ehlers-Danlos syndrome).
explanation: Supports genetic causation of cEDS by COL5A1/COL5A2, but only partially supports biochemical abundance/state.
- reference: PMID:15095409
reference_title: "Reduced type I collagen utilization: a pathogenic mechanism in COL5A1 haplo-insufficient Ehlers-Danlos syndrome."
supports: SUPPORT
snippet: EDS cells with COL5A1 haplo-insufficiency deposited less than one-half of hydroxyproline as collagen compared to control fibroblasts, though total collagen synthesis rates are near-normal because type V collagen represents a small fraction of collagen synthesized.
explanation: The deposition of collagen is significantly reduced in EDS cells with COL5A1 haplo-insufficiency, clearly indicating a biochemical abnormality in collagen type V.
genetic:
- name: COL5A1
association: Pathogenic Variants
inheritance:
- name: Autosomal Dominant
description: A single pathogenic variant inherited from one parent is sufficient to cause disease; most cases are inherited, though de novo mutations occur.
variants:
- name: Missense Mutations
description: Single nucleotide changes resulting in altered amino acid sequence.
- name: Splice Site Mutations
description: Changes affecting mRNA splicing and leading to exon skipping or intronic retention.
- name: Frameshift Mutations
description: Insertions or deletions causing a shift in the reading frame and often resulting in a premature stop codon.
evidence:
- reference: PMID:30858776
reference_title: "New variants in COL5A1 gene among Polish patients with Ehlers-Danlos syndrome: analysis of nine cases."
supports: SUPPORT
snippet: Among all tested patients, nine mutations of COL5A1 gene were detected (8 missense mutations and 1 splice site).
explanation: This reference confirms the existence of missense and splice site mutations in the COL5A1 gene among Ehlers-Danlos Syndrome patients.
- reference: PMID:33656776
reference_title: "Glycine substitution mutation of COL5A1 in classic Ehlers-Danlos syndrome: a case report and literature review."
supports: SUPPORT
snippet: 'Glycine substitution mutation of COL5A1 in classic Ehlers-Danlos syndrome: a case report and literature review.'
explanation: This reference supports the presence of missense mutations specifically related to COL5A1 in Ehlers-Danlos Syndrome.
- reference: PMID:35241120
reference_title: "Association of COL5A1 gene polymorphisms and musculoskeletal soft tissue injuries: a meta-analysis based on 21 observational studies."
supports: PARTIAL
snippet: This study supports that rs12722 is associated with an elevated susceptibility to ligament injury, especially in the Caucasian population.
explanation: While the study primarily investigates the association of COL5A1 polymorphisms with musculoskeletal injuries, it partially supports the statement by recognizing relevant genetic variants.
- reference: PMID:2683783
reference_title: "Inherited disorders of collagen gene structure and expression."
supports: NO_EVIDENCE
snippet: Mutations in the majority of the 20 known collagen genes have not yet been identified.
explanation: This reference doesn't support the existence of frameshift mutations in COL5A1, making the specific part of the statement regarding frameshift mutations unsubstantiated.
- reference: CGGV:assertion_3133eacb-2ef9-4463-8031-11d10f0e91b9-2021-03-24T151331.225Z
reference_title: "COL5A1 / Ehlers-Danlos syndrome, classic type (Definitive)"
supports: SUPPORT
evidence_source: OTHER
snippet: "COL5A1 | HGNC:2209 | Ehlers-Danlos syndrome, classic type | MONDO:0007522 | AD | Definitive"
explanation: ClinGen classifies the COL5A1-Ehlers-Danlos syndrome, classic type gene-disease relationship as definitive with autosomal dominant inheritance.
environmental:
- name: Physical Trauma
description: External mechanical forces including falls, impacts, and repetitive strain that stress the weakened connective tissue.
effect: Exacerbates Symptoms
evidence:
- reference: PMID:26452443
reference_title: "Ehlers-Danlos syndrome(s) mimicking child abuse: Is there an impact on clinical practice?"
supports: PARTIAL
snippet: Ehlers-Danlos syndrome remains undetected until the patient, usually in the pediatric age, shows extensive or severe mucocutaneous injuries after only minor traumas.
explanation: The reference suggests that minor physical trauma can cause severe injuries in patients with Ehlers-Danlos syndrome, which implies an exacerbation of symptoms; however, it does not directly address COL5A1-related cases specifically.
- reference: PMID:34740257
reference_title: "Molecular alterations due to Col5a1 haploinsufficiency in a mouse model of classic Ehlers-Danlos syndrome."
supports: PARTIAL
snippet: Haploinsufficiency of the Col5a1 gene encoding alpha(1) chain of type V collagen is the primary cause of classic Ehlers-Danlos syndrome.
explanation: While the article primarily discusses the genetic cause and molecular mechanisms, it indicates that the structural abnormalities in the extracellular matrix due to COL5A1 deficiency may contribute to symptom exacerbation following physical trauma. However, it does not directly state that physical trauma exacerbates symptoms.
- reference: PMID:36405827
reference_title: "Case report: Lingering post-concussive symptoms in a pediatric patient with presumed Ehlers-Danlos syndrome."
supports: PARTIAL
snippet: Compromised brain tissues and cerebrovasculature could leave these patients vulnerable to mild traumatic brain injury (TBI), with increased severity and duration of post-concussive symptoms and delayed recovery.
explanation: Supports trauma vulnerability in EDS context, but only partially supports this COL5A1-specific environmental effect claim.
treatments:
- name: Supportive Care
description: Management of pain, physical therapy to strengthen joints, and prevention of complications.
evidence:
- reference: PMID:22616833
reference_title: "Ehlers-Danlos syndrome and chronic pain."
supports: PARTIAL
snippet: The topics addressed in this issue are Ehlers-Danlos syndrome and associated chronic pain; the information is meant to help readers understand the mechanisms for pain in this connective tissue disorder as well as general treatment principles for chronic pain management.
explanation: Supports chronic pain management principles in EDS, but only partially supports the full supportive-care descriptor.
- reference: PMID:33741806
reference_title: "Practical management strategies for benign hypermobility syndromes."
supports: SUPPORT
snippet: Evidence supporting physical therapy and occupational therapy is provided... Treatment should be individualized.
explanation: The reference discusses the role of physical therapy in the management of hypermobile Ehlers-Danlos syndromes (hEDS), which aligns with the statement about physical therapy to strengthen joints.
- reference: PMID:9042913
reference_title: "Mutations in the COL5A1 gene are causal in the Ehlers-Danlos syndromes I and II."
supports: NO_EVIDENCE
snippet: These findings confirm the causal role of collagen V in at least a subgroup of EDS I.
explanation: The reference focuses on the genetic aspect and causal mutations in COL5A1 related to Ehlers-Danlos syndrome but does not delve into treatments.
- reference: PMID:35162892
reference_title: "Ehlers-Danlos Syndrome Type Arthrochalasia: A Systematic Review."
supports: NO_EVIDENCE
snippet: Treatment is currently symptomatic and focuses on increasing the quality of life of these patients, as there is no curative treatment.
explanation: The reference mentions symptomatic treatment but does not provide specific details on pain management, physical therapy, or prevention of complications for COL5A1-related Ehlers-Danlos syndrome.
- reference: PMID:32941194
reference_title: "Current management of the vascular subtype of Ehlers-Danlos syndrome."
supports: NO_EVIDENCE
snippet: Although medical interventions to help halt the disease progression remain limited, improved awareness of vEDS by patients and practitioners have resulted in increased average life expectancy.
explanation: The reference discusses limited medical interventions and management of vascular Ehlers-Danlos syndrome (vEDS), which is different from COL5A1-related EDS.
treatment_term:
preferred_term: physical therapy
term:
id: MAXO:0000011
label: physical therapy
- name: Wound Care
description: Careful attention to wound healing and scar management.
evidence:
- reference: PMID:8274350
reference_title: "Understanding Ehlers-Danlos syndrome."
supports: PARTIAL
snippet: Manifestations are highly variable, and include numerous skin abnormalities. Nurses play an important role in helping patients and their families live with this unusual disorder.
explanation: The reference mentions skin abnormalities but does not provide explicit details on treatments related to wound care or scar management.
- reference: PMID:2728341
reference_title: "Cutaneous wound healing in Ehlers-Danlos syndrome."
supports: PARTIAL
snippet: Although delayed wound healing has been reported to be a complication of Ehlers-Danlos syndrome in humans, using clinical and histologic criteria, wound healing in dogs and cats with Ehlers-Danlos syndrome appears to be similar to nonaffected animals.
explanation: This reference discusses wound healing in animal models of EDS but indicates that delayed healing, a common complication in human EDS patients, was not observed in the studied animals.
- reference: PMID:28387435
reference_title: "Collagen V haploinsufficiency in a murine model of classic Ehlers-Danlos syndrome is associated with deficient structural and mechanical healing in tendons."
supports: PARTIAL
snippet: Classic Ehlers-Danlos syndrome (EDS) patients suffer from connective tissue hyperelasticity, joint instability, skin hyperextensibility, tissue fragility, and poor wound healing due to heterozygous mutations in COL5a1 or COL5a2 genes.
explanation: Supports poor wound-healing burden in cEDS, but only indirectly supports wound-care intervention efficacy.
- reference: PMID:37594181
reference_title: "Precision medicine using whole genome sequencing in a cat identifies a novel COL5A1 variant for classical Ehlers-Danlos syndrome."
supports: NO_EVIDENCE
snippet: The classic tragic facial expression was observed as well as chronic pruritus and mild hyperesthesia. ... Histology showed sparse, disorganized collagen and an increase in cutaneous mast cells. Electron microscopy identified ultrastructural defects commonly seen in collagen type V alpha 1 chain (COL5A1) variants including flower-like collagen fibrils in cross-section.
explanation: Snippet describes phenotype/histology and does not directly provide wound-care treatment evidence.
treatment_term:
preferred_term: supportive care
term:
id: MAXO:0000950
label: supportive care
- name: Cardiovascular Monitoring
description: Regular evaluation for mitral valve prolapse and other cardiovascular complications.
evidence:
- reference: PMID:21193204
reference_title: "Cross-sectional and longitudinal assessment of aortic root dilation and valvular anomalies in hypermobile and classic Ehlers-Danlos syndrome."
supports: SUPPORT
snippet: Echocardiography may still be warranted as part of cardiovascular assessment, but decreased frequency of screening is recommended especially in symptom-free adults.
explanation: This reference supports cardiovascular monitoring in Ehlers-Danlos Syndrome, particularly for mitral valve prolapse and aortic dilation.
- reference: PMID:15607555
reference_title: "A novel therapeutic strategy for Ehlers-Danlos syndrome based on nutritional supplements."
supports: PARTIAL
snippet: This proposal is specifically concerned with Ehlers-Danlos syndrome classic type (formerly Types I-III), which is characterized by ... cardiac mitral valve prolapse.
explanation: Supports cardiovascular phenotype association, but only partially supports ongoing monitoring recommendations.
- name: Gastrointestinal Management
description: Treatment of gastroesophageal reflux and other GI symptoms as needed.
evidence:
- reference: PMID:26376608
reference_title: "Ehlers Danlos syndrome and gastrointestinal manifestations: a 20-year experience at Mayo Clinic."
supports: NO_EVIDENCE
snippet: 'CONCLUSIONS & INFERENCES: EDS HM and other subtypes should be considered in patients with chronic functional GI symptoms and abdominal vascular lesions.'
explanation: Snippet supports GI symptom burden in EDS, but does not directly provide treatment evidence for gastrointestinal management.
treatment_term:
preferred_term: gastrointestinal agent therapy
term:
id: MAXO:0000267
label: gastrointestinal agent therapy
- name: Lifestyle Modifications
description: Avoiding high-impact activities and contact sports to prevent injury, and using protective gear when necessary.
evidence:
- reference: PMID:17067502
reference_title: "Ehlers-Danlos syndrome in athletes."
supports: PARTIAL
snippet: Preparticipation cardiothoracic and orthopedic screening is highly recommended for athletes with EDS, and appropriate cardiovascular, orthopedic, gastrointestinal, neurologic, and dermatologic management can often allow patients with EDS to remain active.
explanation: The literature emphasizes careful screening and multidisciplinary management for athletes with EDS, which implicitly supports the avoidance of high-impact activities to prevent injuries but does not explicitly mention the use of protective gear or contact sports.
- reference: PMID:32899328
reference_title: "Psychosocial Influence of Ehlers-Danlos Syndrome in Daily Life of Patients: A Qualitative Study."
supports: PARTIAL
snippet: The major clinical manifestations of EDS include joint hypermobility, skin hyperextensibility, and generalized connective tissue fragility. ... 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.
explanation: The study highlights the importance of providing advice to patients about lifestyle changes due to EDS but does not specifically mention avoiding high-impact activities or using protective gear.
treatment_term:
preferred_term: dietary intervention
term:
id: MAXO:0000088
label: dietary intervention
disease_term:
preferred_term: classic Ehlers-Danlos syndrome
term:
id: MONDO:0007522
label: Ehlers-Danlos syndrome, classic type
Disease Pathophysiology Research Report
Target Disease - Disease Name: Ehlers-Danlos Syndrome, COL5A1-related (classical EDS) - Category: Genetic
Pathophysiology description Classical Ehlers-Danlos syndrome (cEDS) due to COL5A1 variants is a monogenic connective tissue disorder characterized by deficiency or structural abnormality of type V collagen, a minor fibrillar collagen that nucleates and regulates the diameter of type I/III collagen fibrils in skin and other tissues (heterotrimer typically [α1(V)]2α2(V)). Loss or reduction of type V collagen disrupts collagen fibrillogenesis, producing enlarged, heterogeneous, and irregular fibrils, a disorganized ECM architecture, impaired tissue mechanics, and clinical fragility manifested by hyperextensible skin, poor wound healing with atrophic scarring, easy bruising, and generalized joint hypermobility (review and diagnostic guidance) (Zschocke 2024; URL: https://doi.org/10.1515/medgen-2024-2061; Nov 2024) (zschocke2024geneticdiagnosisof pages 2-3). In experimental and translational work, acute or chronic deficiency of Col5a1 in dermal fibroblasts leads to fibrillar disarray on ultrastructure, altered mechanical properties, reduced collagen deposition, prolonged inflammation, and delayed re-epithelialization during wound repair; these defects can be partially rescued by pharmacologic modulation of mechanosensitive integrin signaling or transplantation of wild-type fibroblasts (Kelly‑Scumpia et al., iScience; URL: https://doi.org/10.1016/j.isci.2024.110676; Sep 2024) (kellyscumpia2024modulatingtheextracellular pages 1-2, kellyscumpia2024modulatingtheextracellular pages 2-3).
Core Pathophysiology - Primary mechanisms: COL5A1 pathogenic variants reduce functional type V collagen (often via haploinsufficiency), causing defective nucleation/templating and diameter control of type I/III collagen fibrils. Resultant fibrils show increased mean diameter and irregular composite “collagen cauliflower” structures, with loss of normal basket-weave organization and reduced tissue mechanical integrity (Donahue 2024; 3D model synopsis) (donahue2024athreedimensional(3d) pages 21-26, donahue2024athreedimensional(3d)a pages 21-26, donahue2024athreedimensional(3d)b pages 21-26). Skin AFM imaging demonstrates irregular fibrils and a shift toward lower compressive elastic modulus subpopulations relative to healthy collagen (peak ~2.5 GPa in controls), consistent with weaker fibrils (Neshatian et al., PLOS ONE; URL: https://doi.org/10.1371/journal.pone.0307442; Aug 2024) (neshatian2024investigationofdermal pages 1-2). - Dysregulated pathways: Mechanosensitive integrin signaling is elevated in Col5a1-deficient wounds, and integrin pathway inhibition improves re-epithelialization and reduces inflammation in mice, indicating ECM–integrin mechanotransduction as a driver of healing failure (Kelly‑Scumpia 2024) (kellyscumpia2024modulatingtheextracellular pages 1-2, kellyscumpia2024modulatingtheextracellular pages 2-3). In fibrocartilage pericellular matrix (PCM), Col5a1 haploinsufficiency alters PCM mechanics and cell mechanotransduction, with upregulation of lysyl oxidase and tenascin C biosynthesis in meniscal cells, highlighting a LOX-linked matrix remodeling response to collagen V insufficiency (Wang et al., bioRxiv; URL: https://doi.org/10.1101/2024.06.26.600498; Jun 2024) (royerweeden2023collagenvpromotes pages 1-9). - Affected cellular processes: collagen fibrillogenesis; ECM assembly and organization; cell–matrix adhesion and mechanotransduction; wound-healing programs including re-epithelialization and granulation tissue maturation (Kelly‑Scumpia 2024; Neshatian 2024; Donahue 2024) (kellyscumpia2024modulatingtheextracellular pages 1-2, kellyscumpia2024modulatingtheextracellular pages 2-3, neshatian2024investigationofdermal pages 1-2, donahue2024athreedimensional(3d)a pages 21-26, donahue2024athreedimensional(3d)b pages 21-26).
Key Molecular Players - Genes/Proteins (HGNC): - COL5A1 (HGNC:2199): causal gene for most cEDS, driving Type V collagen deficiency and fibrillogenesis defects (Zschocke 2024; Donahue 2024) (zschocke2024geneticdiagnosisof pages 2-3, donahue2024athreedimensional(3d)a pages 21-26, donahue2024athreedimensional(3d)b pages 21-26). - COL5A2 (HGNC:2200): alternative α2(V) chain; structural variants also implicated in cEDS (Zschocke 2024) (zschocke2024geneticdiagnosisof pages 2-3). - COL1A1 (HGNC:2197): dominant fibrillar collagen partnering with type V in fibrillogenesis; perturbation of type V impacts collagen I fibril nucleation and organization (Donahue 2024; Neshatian 2024) (donahue2024athreedimensional(3d)a pages 21-26, neshatian2024investigationofdermal pages 1-2). - Integrins (e.g., ITGA5/ITGB1): dysregulated expression and signaling in Col5a1-deficient wounds; pharmacologic modulation rescues healing (Kelly‑Scumpia 2024) (kellyscumpia2024modulatingtheextracellular pages 1-2, kellyscumpia2024modulatingtheextracellular pages 2-3). - LOX (lysyl oxidase): upregulated in Col5a1+/D meniscus PCM remodeling; implicated in altered crosslinking responses (Wang 2024) (royerweeden2023collagenvpromotes pages 1-9). - Chemical Entities (CHEBI): - Mechanosensitive integrin pathway inhibitors (small molecules used in murine rescue experiments) are relevant research tools and potential leads for wound-healing modulation in cEDS (Kelly‑Scumpia 2024) (kellyscumpia2024modulatingtheextracellular pages 1-2, kellyscumpia2024modulatingtheextracellular pages 2-3). - Cell Types (CL): dermal fibroblasts (primary Col5a1 source and ECM organizer in skin), keratinocytes (secondary impairment of re-epithelialization), keratocytes/corneal stromal cells (corneal ECM dependence on type V), tenocytes and meniscal fibrochondrocytes (fibrillogenesis/PCM mechanobiology) (Kelly‑Scumpia 2024; Neshatian 2024; Donahue 2024; Wang 2024) (kellyscumpia2024modulatingtheextracellular pages 1-2, kellyscumpia2024modulatingtheextracellular pages 2-3, neshatian2024investigationofdermal pages 1-2, donahue2024athreedimensional(3d)a pages 21-26, royerweeden2023collagenvpromotes pages 1-9). - Anatomical locations (UBERON): skin, corneal stroma, tendons, and meniscus are highlighted as tissues in which type V collagen regulates fibrillogenesis and/or PCM mechanics (Kelly‑Scumpia 2024; Neshatian 2024; Donahue 2024; Wang 2024) (kellyscumpia2024modulatingtheextracellular pages 1-2, neshatian2024investigationofdermal pages 1-2, donahue2024athreedimensional(3d)a pages 21-26, royerweeden2023collagenvpromotes pages 1-9).
Biological Processes (GO terms) disrupted - Collagen fibrillogenesis (GO:0030199): type V is required for nucleation and diameter control of collagen I/III fibrils; loss leads to thickened, irregular, composite fibrils (Donahue 2024; Neshatian 2024) (donahue2024athreedimensional(3d)a pages 21-26, neshatian2024investigationofdermal pages 1-2). - Extracellular matrix organization (GO:0030198): ECM disorganization and reduced mechanical integrity in skin and wounds (Kelly‑Scumpia 2024; Neshatian 2024) (kellyscumpia2024modulatingtheextracellular pages 1-2, neshatian2024investigationofdermal pages 1-2, kellyscumpia2024modulatingtheextracellular pages 2-3). - Wound healing (GO:0042060): delayed re-epithelialization, persistent inflammation, and defective granulation tissue in Col5a1-deficient contexts (Kelly‑Scumpia 2024) (kellyscumpia2024modulatingtheextracellular pages 2-3). - Mechanotransduction/Integrin signaling (GO:0007165/GO:0007229): elevated mechanosensitive integrin pathways in Col5a1-deficient wounds; rescue with integrin modulation (Kelly‑Scumpia 2024); perturbed PCM mechanotransduction in fibrocartilage with Col5a1 haploinsufficiency (Wang 2024) (kellyscumpia2024modulatingtheextracellular pages 1-2, kellyscumpia2024modulatingtheextracellular pages 2-3, royerweeden2023collagenvpromotes pages 1-9).
Cellular Components (GO-CC) - Extracellular matrix (GO:0031012): site of fibrillogenesis defects and mechanical failure in cEDS (Neshatian 2024; Donahue 2024) (neshatian2024investigationofdermal pages 1-2, donahue2024athreedimensional(3d)a pages 21-26). - Pericellular matrix (GO:0071944): collagen V-rich PCM surrounding fibrocartilage cells is mechanically and structurally altered by Col5a1 haploinsufficiency; impacts cell mechanotransduction (Wang 2024) (royerweeden2023collagenvpromotes pages 1-9). - Endoplasmic reticulum (GO:0005783): although many COL5A1 variants are haploinsufficient, dominant-negative effects via ER retention/quality control are general mechanisms in autosomal-dominant ECM diseases and may modulate phenotypes for structural COL5A1 variants (conceptual mechanism; Gariballa 2024; URL: https://doi.org/10.1186/s12929-024-01054-1; Jun 2024) (royerweeden2023collagenvpromotes pages 1-9).
Disease Progression: sequence of events 1) Genotype: COL5A1 pathogenic variant. 2) Molecular consequence: reduced or dysfunctional α1(V) chain; frequently haploinsufficiency → ~50% reduction of type V collagen (Donahue 2024) (donahue2024athreedimensional(3d)a pages 21-26, donahue2024athreedimensional(3d)b pages 21-26). 3) ECM assembly defect: impaired nucleation and control of collagen I/III fibril diameter → increased average fibril diameter, irregular composite fibrils (“cauliflower” morphology), disorganized basket-weave architecture; skin nanomechanics shift to lower modulus populations (Donahue 2024; Neshatian 2024) (donahue2024athreedimensional(3d)a pages 21-26, donahue2024athreedimensional(3d)b pages 21-26, neshatian2024investigationofdermal pages 1-2). 4) Tissue-level changes: reduced tensile integrity and abnormal mechanics; during injury, loose granulation tissue, persistent inflammation, failure of epidermal reconstitution; elevated mechanosensitive integrin signaling (Kelly‑Scumpia 2024) (kellyscumpia2024modulatingtheextracellular pages 2-3, kellyscumpia2024modulatingtheextracellular pages 1-2). 5) Clinical manifestations: hyperextensible skin, atrophic scarring, easy bruising, generalized joint hypermobility; increased risk of wound dehiscence and poor suture retention (Zschocke 2024; Donahue 2024) (zschocke2024geneticdiagnosisof pages 2-3, donahue2024athreedimensional(3d)a pages 21-26, donahue2024athreedimensional(3d)b pages 21-26).
Phenotypic Manifestations (HP terms) - Skin hyperextensibility (HP:0000974), atrophic scarring (HP:0001075), joint hypermobility (HP:0001382), easy bruising (HP:0000978), delayed wound healing (HP:0001030) (Zschocke 2024; Donahue 2024; Kelly‑Scumpia 2024) (zschocke2024geneticdiagnosisof pages 2-3, donahue2024athreedimensional(3d)a pages 21-26, kellyscumpia2024modulatingtheextracellular pages 2-3).
Differences from TNXB-related classical-like EDS (clEDS) - TNXB (Tenascin-X) deficiency causes a recessive classical-like EDS characterized by hyperextensible skin without atrophic scarring, with frequent chronic joint pain/myalgia and neurological features (e.g., paresthesia, axonal polyneuropathy) in reported cohorts and models (Okuda‑Ashitaka & Matsumoto, Frontiers in Genetics; URL: https://doi.org/10.3389/fgene.2023.1107787; Mar 2023). TNXB-related clEDS thus differs from COL5A1-related cEDS, which typically includes atrophic scarring and is autosomal dominant (Okuda‑Ashitaka 2023; Zschocke 2024) (zschocke2024geneticdiagnosisof pages 2-3).
Recent developments and latest research (2023–2024) - Mechanobiology of defective healing: Conditional fibroblast-specific Col5a1 deletion models reveal integrin-dependent mechanotransduction as a targetable axis; integrin inhibitors and fibroblast transplantation improved epidermal gene expression, reduced inflammation, and accelerated closure in mice (iScience, Sep 2024; URL: https://doi.org/10.1016/j.isci.2024.110676) (kellyscumpia2024modulatingtheextracellular pages 1-2, kellyscumpia2024modulatingtheextracellular pages 2-3). - Nanostructure and biomechanics: Skin AFM/Picrosirius methods applied to cEDS show irregular fibrils and reduced modulus subpopulations, supporting nanoscale biomechanical biomarkers (PLOS ONE, Aug 2024; URL: https://doi.org/10.1371/journal.pone.0307442) (neshatian2024investigationofdermal pages 1-2). - PCM mechanobiology: In Col5a1+/D menisci, collagen V insufficiency thickens fibrils and weakens PCM mechanics with altered viscoelasticity, blunting intracellular calcium signaling and upregulating LOX and tenascin C; highlights a pivotal role of collagen V in PCM and mechanotransduction (bioRxiv, Jun 2024; URL: https://doi.org/10.1101/2024.06.26.600498) (royerweeden2023collagenvpromotes pages 1-9). - Reviews/diagnostics: Updated 2024 guidance on genetic diagnosis underscores COL5A1 and COL5A2 as major cEDS genes; transcript analyses can show non-transcription of one allele (null-allele test) supporting haploinsufficiency; no major phenotype differences between LoF and missense in COL5A1 were reported (Medizinische Genetik, Nov 2024; URL: https://doi.org/10.1515/medgen-2024-2061) (zschocke2024geneticdiagnosisof pages 2-3).
Current applications and real-world implementations - Preclinical intervention in murine Col5a1-deficient wound models: integrin-pathway inhibitors (mechanosensitive signaling modulators) and wild-type fibroblast transplantation improved healing parameters (re-epithelialization, closure) (iScience, 2024) (kellyscumpia2024modulatingtheextracellular pages 1-2, kellyscumpia2024modulatingtheextracellular pages 2-3). - Experimental diagnostic adjuncts: skin ultrastructure imaging (TEM), AFM nanomechanics, and Picrosirius red birefringence can visualize ECM disorganization and altered fibrils in cEDS; these methods support research and may complement clinical assessments (PLOS ONE, 2024) (neshatian2024investigationofdermal pages 1-2).
Expert opinions and analysis from authoritative sources - The 2024 diagnostic review emphasizes type V collagen deficiency/abnormality as the central mechanism in cEDS and notes that COL5A1 LoF and missense variants both produce cEDS without strong phenotype stratification; combined sequencing and deletion/duplication testing are recommended, with transcript-level null-allele assessment aiding interpretation (Zschocke 2024) (zschocke2024geneticdiagnosisof pages 2-3). - Mechanobiology-focused experimental work posits that abnormal integrin signaling downstream of ECM disarray is a key driver of impaired healing and inflammation, providing a rationale for pathway-specific interventions (Kelly‑Scumpia 2024) (kellyscumpia2024modulatingtheextracellular pages 1-2, kellyscumpia2024modulatingtheextracellular pages 2-3). - PCM-centric work suggests that collagen V is pivotal in protecting resident fibrocartilage cells from mechanical stress, and its deficiency compromises PCM mechanics and cellular signaling—broadening the pathophysiologic framework beyond skin (Wang 2024) (royerweeden2023collagenvpromotes pages 1-9).
Relevant statistics and data from recent studies - Approximate 50% reduction in type V collagen in COL5A1 haploinsufficiency with an ~25% increase in fibril diameter and abnormal “collagen cauliflower” fibrils reported in cEDS-focused 3D model synthesis (Donahue 2024) (donahue2024athreedimensional(3d)a pages 21-26, donahue2024athreedimensional(3d)b pages 21-26). - AFM nanomechanics: healthy human dermal collagen shows a predominant elastic modulus ~2.5 GPa; cEDS/hEDS samples demonstrate subpopulations with lower modulus, indicating weaker fibrils (PLOS ONE, 2024) (neshatian2024investigationofdermal pages 1-2). - Murine wound outcomes with acute fibroblast-specific Col5a1 deletion: significantly larger wounds (e.g., ~25% unhealed at day 19), delayed re-epithelialization, loose granulation tissue, prolonged inflammation; rescue by integrin modulation or fibroblast transplantation (iScience, 2024) (kellyscumpia2024modulatingtheextracellular pages 2-3).
Gene/protein annotations with ontology terms; phenotype, cell, anatomy, and process mapping | Category | Item | Ontology ID | Evidence/Notes | Sources (pqac IDs) | |---|---|---:|---|---| | Gene / Protein (HGNC) | COL5A1 | HGNC:2199 | Causal gene for cEDS; haploinsufficiency reduces type V collagen, disrupting fibrillogenesis and wound repair (murine and human data). (kellyscumpia2024modulatingtheextracellular pages 2-3, donahue2024athreedimensional(3d)a pages 21-26, zschocke2024geneticdiagnosisof pages 2-3) | pqac-00000005, pqac-00000003, pqac-00000007 | | Gene / Protein (HGNC) | COL5A2 | HGNC:2200 | Alternative type V chain implicated in cEDS; often structural (missense) variants with overlapping phenotype. (zschocke2024geneticdiagnosisof pages 2-3, royerweeden2023collagenvpromotes pages 1-9) | pqac-00000007, pqac-00000006 | | Gene / Protein (HGNC) | COL1A1 | HGNC:2197 | Interacts with type V during fibrillogenesis; COL1A1 variants can produce cEDS-like features and modify phenotype. (donahue2024athreedimensional(3d)a pages 21-26, neshatian2024investigationofdermal pages 1-2) | pqac-00000003, pqac-00000002 | | Gene / Protein (HGNC) | Integrins (e.g., ITGA5 / ITGB1) | (examples) | Altered integrin expression and mechanosensitive integrin signaling observed in Col5a1-deficient wounds; targeting integrins rescues healing in models. (kellyscumpia2024modulatingtheextracellular pages 1-2, kellyscumpia2024modulatingtheextracellular pages 2-3, royerweeden2023collagenvpromotes pages 1-9) | pqac-00000000, pqac-00000005, pqac-00000006 | | Biological Process (GO) | Collagen fibrillogenesis | GO:0030199 | Type V collagen nucleates/limits collagen I/III fibril assembly; loss → increased fibril diameter and irregular "cauliflower" fibrils. (donahue2024athreedimensional(3d)a pages 21-26, neshatian2024investigationofdermal pages 1-2, royerweeden2023collagenvpromotes pages 1-9) | pqac-00000003, pqac-00000002, pqac-00000006 | | Biological Process (GO) | Extracellular matrix organization | GO:0030198 | cEDS shows disorganized ECM architecture and altered matrix mechanics in skin and wounds. (kellyscumpia2024modulatingtheextracellular pages 2-3, donahue2024athreedimensional(3d)a pages 21-26, kellyscumpia2024modulatingtheextracellular pages 1-2) | pqac-00000005, pqac-00000003, pqac-00000000 | | Biological Process (GO) | Wound healing | GO:0042060 | Delayed re-epithelialization, loose granulation tissue, prolonged inflammation in Col5a1 loss models and patient observations. (kellyscumpia2024modulatingtheextracellular pages 2-3, donahue2024athreedimensional(3d)a pages 21-26, kellyscumpia2024modulatingtheextracellular pages 1-2) | pqac-00000005, pqac-00000003, pqac-00000000 | | Biological Process (GO) | Mechanotransduction | GO:0007165 | Altered pericellular mechanics and mechanosensitive signaling (integrins/YAP axis implicated) in Col5a1-deficient contexts. (kellyscumpia2024modulatingtheextracellular pages 1-2, kellyscumpia2024modulatingtheextracellular pages 2-3, royerweeden2023collagenvpromotes pages 1-9) | pqac-00000000, pqac-00000005, pqac-00000006 | | Biological Process (GO) | Integrin signaling pathway | GO:0007229 | Dysregulated integrin expression in wounds; pharmacologic integrin modulation improves outcomes in model systems. (kellyscumpia2024modulatingtheextracellular pages 1-2, kellyscumpia2024modulatingtheextracellular pages 2-3) | pqac-00000000, pqac-00000005 | | Biological Process (GO) | Collagen biosynthetic process | GO:0032964 | Perturbation of collagen V production alters overall collagen matrix deposition and fibril morphology. (donahue2024athreedimensional(3d)a pages 21-26, zschocke2024geneticdiagnosisof pages 2-3) | pqac-00000003, pqac-00000007 | | Cellular Component (GO-CC) | Extracellular matrix | GO:0031012 | Primary compartment where defective collagen V yields disrupted fibril architecture and weaker mechanics (skin AFM/TEM). (neshatian2024investigationofdermal pages 1-2, donahue2024athreedimensional(3d)a pages 21-26) | pqac-00000002, pqac-00000003 | | Cellular Component (GO-CC) | Pericellular matrix | GO:0071944 | Pericellular/pericellular niche altered by reduced ColV production, affecting cell–matrix signaling and protection of cells from mechanical stress. (kellyscumpia2024modulatingtheextracellular pages 2-3, royerweeden2023collagenvpromotes pages 1-9, donahue2024athreedimensional(3d) pages 21-26) | pqac-00000005, pqac-00000006, pqac-00000001 | | Cellular Component (GO-CC) | Endoplasmic reticulum | GO:0005783 | Loss-of-function alleles often produce haploinsufficiency via NMD; ER-related quality control relevant for structural variants (dominant-negative potential). (zschocke2024geneticdiagnosisof pages 2-3) | pqac-00000007 | | Cell Type (CL) | Dermal fibroblast | CL:0002620 | Key source of ColV in skin; fibroblast-specific Col5a1 deletion reproduces cEDS wound defects (reduced migration/proliferation, ECM disarray). (kellyscumpia2024modulatingtheextracellular pages 2-3, donahue2024athreedimensional(3d) pages 21-26) | pqac-00000005, pqac-00000001 | | Cell Type (CL) | Keratinocyte | CL:0000312 | Epidermal gene programs and re-epithelialization impaired secondary to defective dermal ECM in Col5a1-deficient wounds. (kellyscumpia2024modulatingtheextracellular pages 2-3) | pqac-00000005 | | Cell Type (CL) | Keratocyte / corneal stromal cell | CL:0001840 | Corneal wound outcomes affected by ColV deficiency; corneal stromal ECM organization depends on collagen V. (kellyscumpia2024modulatingtheextracellular pages 1-2, donahue2024athreedimensional(3d) pages 21-26) | pqac-00000000, pqac-00000001 | | Cell Type (CL) | Tenocyte / tendon cell | CL:0002304 | Tendon fibrillogenesis and mechanics rely on ColV regulation of fibril diameter; altered cell–matrix interactions reported. (donahue2024athreedimensional(3d)a pages 21-26, royerweeden2023collagenvpromotes pages 1-9) | pqac-00000003, pqac-00000006 | | Cell Type (CL) | Meniscal fibrochondrocyte | CL:0002499 | Type V collagen contributes to pericellular/PCM structure in fibrocartilaginous tissues; Col5a1 perturbation alters PCM mechanics. (royerweeden2023collagenvpromotes pages 1-9, donahue2024athreedimensional(3d) pages 21-26) | pqac-00000006, pqac-00000001 | | Anatomy (UBERON) | Skin of body | UBERON:0002097 | Primary affected organ: skin hyperextensibility, fragility, and altered nanostructure/mechanics documented by AFM and TEM. (neshatian2024investigationofdermal pages 1-2, donahue2024athreedimensional(3d)a pages 21-26, kellyscumpia2024modulatingtheextracellular pages 2-3) | pqac-00000002, pqac-00000003, pqac-00000005 | | Anatomy (UBERON) | Corneal stroma | UBERON:0001772 | ColV important for corneal ECM and wound healing; corneal phenotypes observed in models. (kellyscumpia2024modulatingtheextracellular pages 1-2, donahue2024athreedimensional(3d) pages 21-26) | pqac-00000000, pqac-00000001 | | Anatomy (UBERON) | Tendon | UBERON:0001376 | ColV regulates tendon fibril diameter and mechanics → clinical relevance for joint stability and repair. (donahue2024athreedimensional(3d)a pages 21-26, royerweeden2023collagenvpromotes pages 1-9) | pqac-00000003, pqac-00000006 | | Anatomy (UBERON) | Meniscus of knee | UBERON:0001461 | Fibrocartilaginous tissues show PCM-dependent mechanical changes when Col5a1 is reduced, with implications for load-bearing function. (royerweeden2023collagenvpromotes pages 1-9, donahue2024athreedimensional(3d) pages 21-26) | pqac-00000006, pqac-00000001 | | Phenotype (HPO) | Skin hyperextensibility | HP:0000974 | Core clinical sign of cEDS linked to defective dermal ECM from ColV deficiency. (zschocke2024geneticdiagnosisof pages 2-3, donahue2024athreedimensional(3d)a pages 21-26) | pqac-00000007, pqac-00000003 | | Phenotype (HPO) | Atrophic scarring | HP:0001075 | Delayed/abnormal wound healing with characteristic atrophic "cigarette-paper" scars correlates with fibrillogenesis defects. (donahue2024athreedimensional(3d)a pages 21-26, kellyscumpia2024modulatingtheextracellular pages 2-3) | pqac-00000003, pqac-00000005 | | Phenotype (HPO) | Joint hypermobility | HP:0001382 | Result of connective tissue laxity due to ECM structural weakness from altered collagen V–dependent fibrils. (zschocke2024geneticdiagnosisof pages 2-3, royerweeden2023collagenvpromotes pages 1-9) | pqac-00000007, pqac-00000006 | | Phenotype (HPO) | Easy bruising | HP:0000978 | Tissue fragility and impaired ECM integrity increase bleeding/bruise tendency. (donahue2024athreedimensional(3d)a pages 21-26, neshatian2024investigationofdermal pages 1-2) | pqac-00000003, pqac-00000002 | | Phenotype (HPO) | Delayed wound healing | HP:0001030 | Validated in Col5a1 conditional and haploinsufficient models and observed clinically in cEDS patients. (kellyscumpia2024modulatingtheextracellular pages 2-3, donahue2024athreedimensional(3d)a pages 21-26) | pqac-00000005, pqac-00000003 |
Table: Compact, ontology-mapped annotations for COL5A1-related classical EDS summarizing genes, GO processes, cellular components, cell types, anatomy, and HPO phenotypes with brief evidence notes and source pointers to the gathered contextual items (kellyscumpia2024modulatingtheextracellular pages 1-2, zschocke2024geneticdiagnosisof pages 2-3). This table is useful for knowledge-base population and rapid reference.
Evidence items with PMIDs/DOIs and URLs (selection) - Kelly‑Scumpia KM et al. Modulating the extracellular matrix to treat wound healing defects in Ehlers-Danlos syndrome. iScience. Sep 2024. DOI: 10.1016/j.isci.2024.110676. URL: https://doi.org/10.1016/j.isci.2024.110676 (Mechanosensitive integrin signaling; Col5a1 CKO wound model; rescue) (kellyscumpia2024modulatingtheextracellular pages 1-2, kellyscumpia2024modulatingtheextracellular pages 2-3). - Neshatian M et al. Investigation of dermal collagen nanostructures in EDS patients. PLOS ONE. Aug 2024. DOI: 10.1371/journal.pone.0307442. URL: https://doi.org/10.1371/journal.pone.0307442 (AFM/Picrosirius; irregular fibrils; reduced modulus) (neshatian2024investigationofdermal pages 1-2). - Donahue M. A Three-Dimensional (3D) In Vitro Model of Ehlers-Danlos Syndrome. 2024. (3D model synthesis; haploinsufficiency; fibril diameter; “cauliflowers”; surgical implications) (donahue2024athreedimensional(3d) pages 21-26, donahue2024athreedimensional(3d)a pages 21-26, donahue2024athreedimensional(3d)b pages 21-26). - Wang C et al. Structure-Mechanics Principles and Mechanobiology of Fibrocartilage PCM: A Pivotal Role of Type V Collagen. bioRxiv. Jun 2024. DOI: 10.1101/2024.06.26.600498. URL: https://doi.org/10.1101/2024.06.26.600498 (Col5a1+/D meniscus; PCM mechanics; LOX/TNC upregulation) (royerweeden2023collagenvpromotes pages 1-9). - Zschocke J et al. Genetic diagnosis of the Ehlers-Danlos syndromes. Medizinische Genetik. Nov 2024. DOI: 10.1515/medgen-2024-2061. URL: https://doi.org/10.1515/medgen-2024-2061 (diagnostic guidance; COL5A1/COL5A2; null-allele testing; clinical features) (zschocke2024geneticdiagnosisof pages 2-3). - Okuda‑Ashitaka E, Matsumoto K‑i. Tenascin-X as a causal gene for classical-like EDS. Frontiers in Genetics. Mar 2023. DOI: 10.3389/fgene.2023.1107787. URL: https://doi.org/10.3389/fgene.2023.1107787 (TNXB clEDS; lack of atrophic scarring; neurological features) (zschocke2024geneticdiagnosisof pages 2-3).
Notes on evidence scope - The strongest 2023–2024 mechanistic evidence for COL5A1-related cEDS centers on fibrillogenesis/ECM disorganization, mechanosensitive integrin signaling in wound repair, and PCM mechanobiology; detailed TGF‑β and autophagy/ER stress pathway data specific to COL5A1-related cEDS were not identified in the gathered 2023–2024 sources and remain an area for future targeted review. Where ER retention/dominant-negative mechanisms are discussed, they are presented as general principles in autosomal-dominant ECM disorders rather than COL5A1-specific demonstrations (Gariballa 2024) (royerweeden2023collagenvpromotes pages 1-9).
Summary COL5A1-related cEDS is driven by type V collagen deficiency or structural dysfunction, impairing collagen I/III fibrillogenesis and pericellular matrix mechanics. This produces disorganized ECM with weaker fibrils, abnormal mechanotransduction, and impaired wound repair, clinically expressed as hyperextensible skin, atrophic scarring, easy bruising, and joint hypermobility. Recent studies highlight integrin-pathway dysregulation and PCM mechanics as mechanistic nodes and preclinical therapeutic targets, while diagnostics emphasize comprehensive COL5A1/COL5A2 testing with transcript-level assessments for haploinsufficiency (Zschocke 2024; Kelly‑Scumpia 2024; Wang 2024; Neshatian 2024) (zschocke2024geneticdiagnosisof pages 2-3, kellyscumpia2024modulatingtheextracellular pages 1-2, royerweeden2023collagenvpromotes pages 1-9, neshatian2024investigationofdermal pages 1-2).
References
(zschocke2024geneticdiagnosisof pages 2-3): Johannes Zschocke, Serwet Demirdas, and Fleur S. van Dijk. Genetic diagnosis of the ehlers-danlos syndromes. Medizinische Genetik, 36:235-245, Nov 2024. URL: https://doi.org/10.1515/medgen-2024-2061, doi:10.1515/medgen-2024-2061. This article has 3 citations and is from a poor quality or predatory journal.
(kellyscumpia2024modulatingtheextracellular pages 1-2): Kindra M. Kelly-Scumpia, Maani M. Archang, Prabhat K. Purbey, Tomohiro Yokota, Rimao Wu, Jackie McCourt, Shen Li, Rachelle H. Crosbie, Philip O. Scumpia, and Arjun Deb. Modulating the extracellular matrix to treat wound healing defects in ehlers-danlos syndrome. iScience, 27:110676, Sep 2024. URL: https://doi.org/10.1016/j.isci.2024.110676, doi:10.1016/j.isci.2024.110676. This article has 5 citations and is from a peer-reviewed journal.
(kellyscumpia2024modulatingtheextracellular pages 2-3): Kindra M. Kelly-Scumpia, Maani M. Archang, Prabhat K. Purbey, Tomohiro Yokota, Rimao Wu, Jackie McCourt, Shen Li, Rachelle H. Crosbie, Philip O. Scumpia, and Arjun Deb. Modulating the extracellular matrix to treat wound healing defects in ehlers-danlos syndrome. iScience, 27:110676, Sep 2024. URL: https://doi.org/10.1016/j.isci.2024.110676, doi:10.1016/j.isci.2024.110676. This article has 5 citations and is from a peer-reviewed journal.
(donahue2024athreedimensional(3d) pages 21-26): M Donahue. A three-dimensional (3d) in vitro model of ehlers-danlos syndrome. Unknown journal, 2024.
(donahue2024athreedimensional(3d)a pages 21-26): M Donahue. A three-dimensional (3d) in vitro model of ehlers-danlos syndrome. Unknown journal, 2024.
(donahue2024athreedimensional(3d)b pages 21-26): M Donahue. A three-dimensional (3d) in vitro model of ehlers-danlos syndrome. Unknown journal, 2024.
(neshatian2024investigationofdermal pages 1-2): Mehrnoosh Neshatian, Nimish Mittal, Sophia Huang, Aiman Ali, Emilie Khattignavong, and Laurent Bozec. Investigation of dermal collagen nanostructures in ehlers-danlos syndrome (eds) patients. PLOS ONE, 19:e0307442, Aug 2024. URL: https://doi.org/10.1371/journal.pone.0307442, doi:10.1371/journal.pone.0307442. This article has 5 citations and is from a peer-reviewed journal.
(royerweeden2023collagenvpromotes pages 1-9): Shaina P. Royer-Weeden. Collagen v promotes fibroblast contractility, and adhesion formation, and stability. ArXiv, 2023. URL: https://doi.org/10.37099/mtu.dc.etdr/1647, doi:10.37099/mtu.dc.etdr/1647. This article has 0 citations.