| Property | Value | [@gould2006] |----------|-------| [@biffi2010] | Gene Symbol | COL4A2 | [@poschl2004] | Full Name | Collagen Type IV Alpha 2 Chain | [@joutel2010] | Aliases | ICH, POREN2 | | Chromosomal Location | 13q34 | | NCBI Gene ID | [1284](https://www.ncbi.nlm.nih.gov/gene/1284) | | OMIM ID | [120090](https://omim.org/entry/120090) | | Ensembl ID | [ENSG00000134871](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000134871) | | UniProt ID | [P08572](https://www.uniprot.org/uniprot/P08572) | | Encoded Protein | [Collagen IV α2 chain](/proteins/col4a2-protein) | | Associated Diseases | Cerebral small vessel disease, porencephaly, intracerebral hemorrhage, HANAC syndrome |
</div>
Overview
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title: COL4A2 Gene
COL4A2 (Collagen Type IV Alpha 2 Chain)
<div class="infobox infobox-gene"> [@kuo2012]
| Property | Value | [@gould2006] |----------|-------| [@biffi2010] | Gene Symbol | COL4A2 | [@poschl2004] | Full Name | Collagen Type IV Alpha 2 Chain | [@joutel2010] | Aliases | ICH, POREN2 | | Chromosomal Location | 13q34 | | NCBI Gene ID | [1284](https://www.ncbi.nlm.nih.gov/gene/1284) | | OMIM ID | [120090](https://omim.org/entry/120090) | | Ensembl ID | [ENSG00000134871](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000134871) | | UniProt ID | [P08572](https://www.uniprot.org/uniprot/P08572) | | Encoded Protein | [Collagen IV α2 chain](/proteins/col4a2-protein) | | Associated Diseases | Cerebral small vessel disease, porencephaly, intracerebral hemorrhage, HANAC syndrome |
</div>
Overview
COL4A2 is a human gene whose product cOL4A2** encodes the alpha-2 chain of type IV collagen, a major structural component of basement membranes throughout the body. Type IV collagen is the most abundant component of all basement membranes, forming a network that provides structural support and serves as a scaffold for other basement membrane proteins. In the central nervous system, collagen IV is a critical component of the cerebrovascular basement membrane, the [blood-brain barrier](/entities/blood-brain-barrier) (BBB), and the neurovascular unit. Variants in COL4A2 have been implicated in Cerebral Small Vessel Disease (CSVD), Porencephaly (POREN2), Intracerebral Hemorrhage (ICH). This page covers the gene's normal function, disease associations, expression patterns, and key research findings relevant to neurodegeneration.
Function
COL4A2 encodes the alpha-2 chain of type IV collagen, a major structural component of basement membranes throughout the body. Type IV collagen is the most abundant component of all basement membranes, forming a network that provides structural support and serves as a scaffold for other basement membrane proteins. In the central nervous system, collagen IV is a critical component of the cerebrovascular basement membrane, the blood-brain barrier (BBB), and the neurovascular unit.
Key normal physiological functions include:
Basement membrane integrity — The α1α1α2(IV) protomer (two [COL4A1](/genes/col4a1) chains + one COL4A2 chain) is the predominant collagen IV isoform in cerebrovascular basement membranes, providing structural integrity to blood vessels
Blood-brain barrier (BBB) maintenance — Collagen IV in the vascular basement membrane provides the structural scaffold for the [BBB](/mechanisms/blood-brain-barrier), supporting [endothelial cells](/cell-types/endothelial-cells), [pericytes](/cell-types/pericytes), and [astrocyte](/cell-types/astrocytes) endfeet
Angiogenesis and vascular development — Required for proper cerebrovascular development; interacts with integrins and growth factor receptors on endothelial cells
Cell signaling scaffold — Collagen IV binds and presents growth factors (VEGF, PDGF, FGF) to cell surface receptors, modulating signaling
Neurovascular unit support — Maintains the structural relationship between [neurons](/entities/neurons), glia, and blood vessels essential for neurovascular coupling and cerebral autoregulation
Disease Associations
Cerebral Small Vessel Disease (CSVD)
COL4A2 mutations are an important genetic cause of cerebral small vessel disease, a leading contributor to stroke and vascular dementia:
Pathomechanism — Mutations in COL4A2 destabilize the collagen IV triple helix, causing intracellular accumulation of misfolded procollagen in the endoplasmic reticulum and reduced basement membrane collagen IV deposition
Clinical spectrum — Ranges from severe neonatal porencephaly to adult-onset lacunar strokes and leukoaraiencephalopathy
Overlap with [COL4A1](/genes/col4a1) — Since COL4A1 and COL4A2 form obligate heterotrimers, mutations in either gene cause overlapping phenotypes
Porencephaly (POREN2)
COL4A2 mutations cause porencephaly type 2, a severe brain malformation:
Pathogenesis — Basement membrane fragility leads to cerebrovascular rupture during fetal development or the perinatal period
Features — Fluid-filled cystic cavities in the brain parenchyma communicating with the ventricular system
Severity — Ranges from focal porencephaly to extensive bilateral cysts with severe neurological deficits
Inheritance — Autosomal dominant with variable expressivity; de novo mutations are common
Mutations — Typically missense mutations affecting glycine residues in the Gly-X-Y repeat (e.g., G702D, G693E, G1389R)
Intracerebral Hemorrhage (ICH)
COL4A2 variants contribute to sporadic intracerebral hemorrhage:
Common variants — GWAS have identified COL4A2 common variants associated with ICH risk, particularly deep ICH
Mechanism — Reduced collagen IV deposition weakens small vessel walls, predisposing to rupture
Age-dependent penetrance — ICH risk from COL4A2 variants increases with age and is compounded by hypertension
Interaction with other risk factors — COL4A2 variants synergize with hypertension, cerebral amyloid angiopathy ([CAA](/diseases/cerebral-amyloid-angiopathy)), and anticoagulant use
HANAC Syndrome
Hereditary Angiopathy with Nephropathy, Aneurysms, and muscle Cramps:
Systemic collagen IV disorder — Primarily associated with [COL4A1](/genes/col4a1) mutations, but COL4A2 mutations can cause overlapping features
Neurological features — Cerebral aneurysms, white matter hyperintensities, migraine with aura
COL4A2 has emerging connections to neurodegeneration beyond acute cerebrovascular events:
Vascular contributions to cognitive impairment and dementia (VCID) — Chronic cerebrovascular basement membrane dysfunction contributes to [vascular dementia](/diseases/vascular-dementia) and mixed-pathology [Alzheimer's disease](/diseases/alzheimers-disease)
Blood-brain barrier breakdown — Collagen IV deficiency compromises BBB integrity, allowing entry of plasma proteins and inflammatory mediators into the brain parenchyma, driving [neuroinflammation](/mechanisms/neuroinflammation)
Impaired Aβ clearance — The perivascular drainage pathway for [amyloid-beta](/proteins/amyloid-beta) clearance depends on intact basement membranes; collagen IV disruption impairs this clearance route, potentially promoting [cerebral amyloid angiopathy](/diseases/cerebral-amyloid-angiopathy)
Neurovascular unit dysfunction — Basement membrane disruption uncouples neurons from their blood supply, contributing to chronic hypoperfusion and neurodegeneration
Expression
COL4A2 is broadly expressed with high levels in vascular tissues:
Cellular expression in the brain: [Endothelial cells](/cell-types/endothelial-cells), [pericytes](/cell-types/pericytes), [astrocyte](/cell-types/astrocytes) endfeet (all components of the neurovascular unit produce collagen IV)
Subcellular: Synthesized in the ER, assembled into triple-helical protomers, secreted, and incorporated into the extracellular basement membrane
Developmental: Expression begins early in embryogenesis; critical for vascular development from E8.5 in mice
Gene Structure and Regulation
Gene size: ~220 kb spanning 48 exons (one of the larger collagen genes)
Head-to-head arrangement: COL4A2 and [COL4A1](/genes/col4a1) are arranged head-to-head on chromosome 13q34, sharing a bidirectional promoter
Shared promoter: The ~130 bp bidirectional promoter drives coordinate expression of both genes, ensuring stoichiometric production of α1 and α2 chains
Regulatory elements: Responsive to hypoxia (HIF-1α binding sites), TGF-β signaling, and mechanical stress
Transcript: ~6.5 kb mRNA encoding a 1,712-amino acid preprotein
Animal Models
Col4a2 mutant mice — Several ENU-induced and targeted mutations recapitulate human disease:
Heterozygous mice develop age-dependent cerebrovascular disease, ICH, and porencephaly
Severity depends on genetic background, demonstrating modifier gene effects
Homozygous null mutations are embryonic lethal (E10.5-11.5) due to basement membrane failure
Col4a1/Col4a2 compound heterozygotes — Show more severe phenotypes than single-gene mutants, confirming dosage sensitivity
[Jeanne et al., COL4A2 mutations impair COL4A1 and COL4A2 secretion and cause hemorrhagic stroke (2012) (2012)](https://doi.org/10.1016/j.ajhg.2012.09.002)
[Verbeek et al., COL4A2 mutation associated with familial porencephaly and small-vessel disease (2012) (2012)](https://doi.org/10.1038/ejhg.2012.49)
[Rannikmae et al., COL4A2 is associated with lacunar ischaemic stroke and deep ICH (2017) (2017)](https://doi.org/10.1212/WNL.0000000000003659)
[Kuo et al., Collagen IV mutation causes cerebrovascular disease and BBB defects (2012) (2012)](https://doi.org/10.1093/hmg/dds225)
[Gould et al., Role of COL4A1 in small-vessel disease and hemorrhagic stroke (2006) (2006)](https://doi.org/10.1056/NEJMoa053727)
[Biffi et al., Variants at APOE influence risk of deep and lobar intracerebral hemorrhage (2010) (2010)](https://doi.org/10.1002/ana.22167)
[Poschl et al., Collagen IV is essential for basement membrane stability but dispensable for initiation of its assembly during early development (2004) (2004)](https://doi.org/10.1242/dev.01072)
[Joutel et al., Cerebrovascular dysfunction and microcirculation rarefaction precede white matter lesions in a mouse genetic model of cerebral ischemic small vessel disease (2010) (2010)](https://doi.org/10.1172/JCI39799)