Role of COL4A1 in basement-membrane integrity and cerebral small-vessel disease. The COL4A1 stroke syndrome.
ABSTRACT Type IV collagens are basement membrane (BM) proteins expressed in all tissues including the vasculature. COL4A1 and COL4A2, the most abundant type IV collagens, form heterotrimers with a 2:1 stoichiometry and each heterotrimer forms a triple helix along the length of the collagenous domains. Recently, mutations in COL4A1 on chromosome 13q34, encoding the alpha1 chain of type IV collagen, have been linked to a spectrum of cerebral small-vessel disease in humans, including perinatal intracerebral hemorrhage (ICH) with consequent porencephaly, adult-onset ICH, microbleeds, lacunar strokes, and leukoaraiosis, which follows an autosomal dominant pattern of inheritance. This variable phenotype has been named the "COL4A1 stroke syndrome". In COL4A1 stroke syndrome most mutations are missense mutations involving a glycine residue, including G562E, G749S, G805R, G1130D, G1236R, G1423R, G720D, G1580R, and G755R. Mutations replacing a highly conserved hydrophobic glycine residue likely lead to synthesis of an abnormal protein with abnormal structure and inhibit heterotrimer secretion into the vascular BM, modify its structural properties (when imaged with electron microscopy BM is uneven, with inconsistent density and focal disruptions), and, thus, increase the fragility of the vessel wall when exposed to environmental factors. Although pathological changes in BM also occur in other tissues (mostly retina and kidney), the major site of vessel damage is the brain. In the present review article we will focus on the molecular basis of the COL4A1 stroke syndrome, summarize data on its variable phenotype, and explore additional questions concerning the possible genotype-phenotype correlations and the mechanisms leading to cerebral small-vessel disease in this clinically heterogeneous condition.
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ABSTRACT: COL4A1 is located in humans on chromosome13q34 and it encodes the alpha 1 chain of type IV collagen, a component of basal membrane. It is expressed mainly in the brain, muscles, kidneys and eyes. Different COL4A1 mutations have been reported in many patients who present a very wide spectrum of clinical symptoms. They typically show a multisystemic phenotype. Here we report on the case of a patient carrying a novel de novo splicing mutation of COL4A1 associated with a distinctive clinical picture characterized by onset in infancy and an unusual evolution of the neuroradiological features. At three months of age, the child was diagnosed with a congenital cataract, while his brain MRI was normal. Over the following years, the patient developed focal epilepsy, mild diplegia, asymptomatic microhematuria, raised creatine kinase levels, MRI white matter abnormalities and brain calcification on CT. During the neuroradiological follow-up the extension and intensity of the brain lesions progressively decreased. The significance of a second variant in COL4A1 carried by the child and inherited from his father remains to be clarified. In conclusion, our patient shows new aspects of this collagenopathy and possibly a COL4A1 compound heterozygosity. © 2015 Wiley Periodicals, Inc. © 2014 Wiley Periodicals, Inc.American Journal of Medical Genetics Part A 02/2015; 167(4). DOI:10.1002/ajmg.a.36907 · 2.05 Impact Factor
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ABSTRACT: Background We know the influence of the intravitreal anti-vascular endothelial growth factor (VEGF) injections on the choroidal neovascularization in the course of exudative age-related macular degeneration (AMD). However, the influence of the ranibizumab therapy in question on the extracellular matrix (ECM) remains unknown. We aimed to estimate the influence of Lucentis intravitreal injections on the gene expression of structural components of the extracellular matrix in patients with neovascular AMD. Material/Methods Patients with subfoveal localization of neovascularization in AMD, which was clinically active and observed using optical coherence tomography, were treated with ranibizumab (0.5 mg/0.05 mL) in accordance with the PrONTO scheme. Total RNA was extracted from peripheral blood mononuclear cells, and an oligonucleotide microarray technique enabled comparison of the expression level of genes encoding collagens, elastin, and laminins in AMD patients compared to control subjects. Results After 3 intravitreal injections of ranibizumab (Lucentis), COL1A1 and COL6A1 genes showed increased expression, whereas decreased expression mainly occurred for the following genes: COL4A5, COL11A1, COL4A6, LAMB4, and LAMC2. Conclusions Anti-VEGF local therapy influences the gene expression of structural components of the ECM as measured from blood samples. The loading dose of ranibizumab for the retina changes the expression of collagen and laminin genes, but does not influence the expression of the elastin gene.Medical science monitor: international medical journal of experimental and clinical research 05/2014; 20:875-83. DOI:10.12659/MSM.890031 · 1.22 Impact Factor
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ABSTRACT: Small vessel diseases (SVDs) of the brain are likely to become increasingly common in tandem with the rise in the aging population. In recent years, neuroimaging and pathological studies have informed on the pathogenesis of sporadic SVD and several single gene (monogenic) disorders predisposing to subcortical strokes and diffuse white matter disease. However, one of the limitations toward studying SVD lies in the lack of consistent assessment criteria and lesion burden for both clinical and pathological measures. Arteriolosclerosis and diffuse white matter changes are the hallmark features of both sporadic and hereditary SVDs. The pathogenesis of the arteriopathy is the key to understanding the differential progression of disease in various SVDs. Remarkably, quantification of microvascular abnormalities in sporadic and hereditary SVDs has shown that qualitatively the processes involved in arteriolar degeneration are largely similar in sporadic SVD compared with hereditary disorders such as cerebral autosomal arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Important significant regional differences in lesion location within the brain may enable one to distinguish SVDs, where frontal lobe involvement appears consistently with almost every SVD, but others bear specific pathologies in other lobes, such as the temporal pole in CADASIL and the pons in pontine autosomal dominant microangiopathy and leukoencephalopathy or PADMAL. Additionally, degenerative changes in the vascular smooth muscle cells, the cerebral endothelium and the basal lamina are often rapid and more aggressive in genetic disorders. Further quantification of other microvascular elements and even neuronal cells is needed to fully characterize SVD pathogenesis and to differentiate the usefulness of vascular interventions and treatments on the resulting pathology.Brain Pathology 09/2014; 24(5). DOI:10.1111/bpa.12177 · 4.35 Impact Factor