COL4A1 mutation in Axenfeld-Rieger anomaly with leukoencephalopathy and stroke

Centre Hospitalier Universitaire Bordeaux, Fédération des Neurosciences Cliniques, Hôpital Pellegrin, Bordeaux, France.
Annals of Neurology (Impact Factor: 9.98). 08/2007; 62(2):177-84. DOI: 10.1002/ana.21191
Source: PubMed


Several hereditary ischemic small-vessel diseases of the brain have been reported during the last decade. Some of them have ophthalmological, mainly retinal, manifestations. Herein, we report on a family affected by vascular leukoencephalopathy and variable abnormalities of the anterior chamber of the eye.
After the occurrence of a small, deep infarct associated with white matter lesions in a patient with a medical history of congenital cataract and amblyopia, we conducted clinical and neuroradiological investigations in 10 of her relatives.
Diffuse leukoencephalopathy associated with ocular malformations of the Axenfeld-Rieger type was observed in five individuals. Familial genetic analyses led to the identification of a novel missense mutation in the COL4A1 gene, p.G720D, which cosegregates with the disease.
Our data corroborate previous observations demonstrating the role of COL4A1 in cerebral microangiopathy and expand the phenotypic spectrum associated with mutations in this gene. We delineate a novel association between the Axenfeld-Rieger anomaly and leukoencephalopathy and stroke. Ann Neurol 2007.

1 Follower
39 Reads
  • Source
    • "E-mail: Article first published online in Wiley Online Library ( 00 Month 2014 DOI 10.1002/ajmg.a.36907 Ó 2015 Wiley Periodicals, Inc. et al., 2006; Sibon et al., 2007; Vahedi et al., 2007; Alamowitch et al., 2009; Bilguvar et al., 2009; De Vries et al., 2009, Shah et al., 2010; Livingston et al., 2011; Meuwissen et al., 2011; Tonduti et al., 2012; Lemmens et al., 2013] "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Feb 2015 · American Journal of Medical Genetics Part A
  • Source
    • "For example, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most common inherited cause of vascular dementia [12], is caused by mutations in NOTCH3 [13], a gene preferentially expressed in vascular smooth muscle [14], [15]. Furthermore, mutations in COL4A1, a gene encoding the main component of smooth muscle basement membranes, also causes SVD in families with inherited leukoencephalopathy [16], [17], [18]. Pathways by which mutant NOTCH3 and COL4A1 lead to smooth muscle dysfunction and SVD are under active investigation. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Von Willebrand factor (vWF), a hemostatic protein normally synthesized and stored by endothelial cells and platelets, has been localized beyond the endothelium in vascular disease states. Previous studies have implicated potential non-hemostatic functions of vWF, but signaling mechanisms underlying its effects are currently undefined. We present evidence that vWF breaches the endothelium and is expressed in a transmural distribution pattern in cerebral small vessel disease (SVD). To determine the potential molecular consequences of vWF permeation into the vessel wall, we also tested whether vWF impairs Notch regulation of key smooth muscle marker genes. In a co-culture system using Notch ligand expressing cells to stimulate Notch in A7R5 cells, vWF strongly inhibited both the Notch pathway and the activation of mature smooth muscle gene promoters. Similar repressive effects were observed in primary human cerebral vascular smooth muscle cells. Expression of the intracellular domain of NOTCH3 allowed cells to bypass the inhibitory effects of vWF. Moreover, vWF forms molecular complexes with all four mammalian Notch ectodomains, suggesting a novel function of vWF as an extracellular inhibitor of Notch signaling. In sum, these studies demonstrate vWF in the vessel wall as a common feature of cerebral SVD; furthermore, we provide a plausible mechanism by which non-hemostatic vWF may play a novel role in the promotion of vascular disease.
    Preview · Article · Sep 2013 · PLoS ONE
  • Source
    • "Therefore, it comes of no surprise that disturbances of collagen expression is related to severe disorders, such as HANAC (Hereditary Angiopathy, Nephropathy, Aneurysms, and Cramps) syndrome, a COL4A1-related disorder that presents with retinal tortuosity and muscle cramps and with variable combinations of small vessel brain disease [56], or the “COL4A1 stroke syndrome” [81]. Furthermore, COL4A1 malfunction has been associated with cerebral microangiopathy, the Axenfeld-Rieger anomaly, and leukoencephalopathy and stroke [71]. Collagen XV is pivotal to peripheral nerve maturation. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Inaccurate wiring and synaptic pathology appear to be major hallmarks of schizophrenia. A variety of gene products involved in synaptic neurotransmission and receptor signaling are differentially expressed in brains of schizophrenia patients. However, synaptic pathology may also develop by improper expression of intra- and extra-cellular structural elements weakening synaptic stability. Therefore, we have investigated transcription of these elements in the left superior temporal gyrus of 10 schizophrenia patients and 10 healthy controls by genome-wide microarrays (Illumina). Fourteen up-regulated and 22 downregulated genes encoding structural elements were chosen from the lists of differentially regulated genes for further qRT-PCR analysis. Almost all genes confirmed by this method were downregulated. Their gene products belonged to vesicle-associated proteins, that is, synaptotagmin 6 and syntaxin 12, to cytoskeletal proteins, like myosin 6, pleckstrin, or to proteins of the extracellular matrix, such as collagens, or laminin C3. Our results underline the pivotal roles of structural genes that control formation and stabilization of pre- and post-synaptic elements or influence axon guidance in schizophrenia. The glial origin of collagen or laminin highlights the close interrelationship between neurons and glial cells in establishment and maintenance of synaptic strength and plasticity. It is hypothesized that abnormal expression of these and related genes has a major impact on the pathophysiology of schizophrenia. Electronic supplementary material The online version of this article (doi:10.1007/s00406-012-0306-y) contains supplementary material, which is available to authorized users.
    Full-text · Article · Mar 2012 · European Archives of Psychiatry and Clinical Neuroscience
Show more