COL4A2 mutation associated with familial porencephaly and small-vessel disease

Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
European journal of human genetics: EJHG (Impact Factor: 4.35). 02/2012; 20(8):844-51. DOI: 10.1038/ejhg.2012.20
Source: PubMed

ABSTRACT Familial porencephaly, leukoencephalopathy and small-vessel disease belong to the spectrum of disorders ascribed to dominant mutations in the gene encoding for type IV collagen alpha-1 (COL4A1). Mice harbouring mutations in either Col4a1 or Col4a2 suffer from porencephaly, hydrocephalus, cerebral and ocular bleeding and developmental defects. We observed porencephaly and white matter lesions in members from two families that lack COL4A1 mutations. We hypothesized that COL4A2 mutations confer genetic predisposition to porencephaly, therefore we sequenced COL4A2 in the family members and characterized clinical, neuroradiological and biochemical phenotypes. Genomic sequencing of COL4A2 identified the heterozygous missense G1389R in exon 44 in one family and the c.3206delC change in exon 34 leading to frame shift and premature stop, in the second family. Fragmentation and duplication of epidermal basement membranes were observed by electron microscopy in a c.3206delC patient skin biopsy, consistent with abnormal collagen IV network. Collagen chain accumulation and endoplasmic reticulum (ER) stress have been proposed as cellular mechanism in COL4A1 mutations. In COL4A2 (3206delC) fibroblasts we detected increased rates of apoptosis and no signs of ER stress. Mutation phenotypes varied, including porencephaly, white matter lesions, cerebellar and optic nerve hypoplasia and unruptured carotid aneurysm. In the second family however, we found evidence for additional factors contributing to the phenotype. We conclude that dominant COL4A2 mutations are a novel major risk factor for familial cerebrovascular disease, including porencephaly and small-vessel disease with reduced penetrance and variable phenotype, which might also be modified by other contributing factors.

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    • "The absence of extra-vascular defects and the reduced penetrance of the porencephaly strongly suggest that COL4A2 mutations result in a disease of reduced severity and/or affect only a subset of organs compared with COL4A1 mutations. This is supported by data from mouse models and other families (21–23). Moreover, the reduced penetrance implies that in the absence of an extensive family history, familial haemorrhagic stroke caused by COL4A2 mutations might be mistakenly classified as sporadic. "
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    ABSTRACT: Haemorrhagic stroke accounts for approximately 20% of stroke cases and porencephaly is a clinical consequence of perinatal cerebral haemorrhaging. Here we report the identification of a novel dominant G702D mutation in the collagen domain of COL4A2 (collagen IV alpha chain 2) in a family displaying porencephaly with reduced penetrance. COL4A2 is the obligatory protein partner of COL4A1 but in contrast to most COL4A1 mutations, the COL4A2 mutation does not lead to eye or kidney disease. Analysis of dermal biopsies from patient and his unaffected father, who also carries the mutation, revealed that both display basement membrane (BM) defects. Intriguingly, defective collagen IV incorporation into the dermal BM was only observed in the patient and was associated with endoplasmic reticulum (ER) retention of COL4A2 in primary dermal fibroblasts. This intracellular accumulation led to ER-stress, unfolded protein response activation, reduced cell proliferation and increased apoptosis. Interestingly, absence of ER retention of COL4A2 and ER-stress in cells from the unaffected father indicate that accumulation and/or clearance of mutant COL4A2 from the ER may be a critical modifier for disease development. Our analysis also revealed that mutant collagen IV is degraded via the proteasome. Importantly, treatment of patient cells with a chemical chaperone decreased intracellular COL4A2, ER-stress and apoptosis, demonstrating that reducing intracellular collagen accumulation can ameliorate the cellular phenotype of COL4A2 mutations. Importantly, these data highlight that manipulation of chaperone levels, intracellular collagen accumulation and ER-stress are potential therapeutic options for collagen IV diseases including haemorrhagic stroke.
    Human Molecular Genetics 09/2013; 23(2). DOI:10.1093/hmg/ddt418 · 6.39 Impact Factor
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    ABSTRACT: Heterotrimers composed of collagen type IV alpha 1 (COL4A1) and alpha 2 (COL4A2) constitute one of the most abundant components of nearly all basement membranes. Accordingly, mutations in COL4A1 or COL4A2 are pleiotropic and contribute to a broad spectrum of disorders, including myopathy, glaucoma and hemorrhagic stroke. Here, we summarize the contributions of COL4A1 and COL4A2 mutations in human disease, integrate knowledge gained from model organisms and evaluate the implications for pathogenic mechanisms and therapeutic approaches.
    Human Molecular Genetics 08/2012; 21(R1):R97-R110. DOI:10.1093/hmg/dds346 · 6.39 Impact Factor
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    ABSTRACT: Mutations in COL4A1 have been identified in families with hereditary small vessel disease of the brain presumably due to a dominant negative mechanism. Here we report on two novel mutations in COL4A1 in two families with porencephaly, intracerebral hemorrhage and severe white matter disease caused by haploinsufficiency.Two families with various clinical presentations of cerebral microangiopathy and autosomal dominant inheritance were examined. Clinical, neuroradiological and genetic investigations were performed. Electron microscopy of the skin was also performed.In one of the families, sequence analysis revealed a one base deletion, c.2085del, leading to a frameshift and a premature stopcodon, p.(Gly696fs). In the other family, a splice site mutation was identified, c.2194-1G>A, which most likely leads to skipping of an exon with a frameshift and premature termination as a result. In fibroblasts of affected individuals from both families nonsense mediated decay of the mutant COL4A1 mRNAs and a clear reduction of COL4A1 protein expression was demonstrated, indicating haploinsufficiency of COL4A1. Moreover thickening of the capillary basement membrane in the skin was documented, similar to reports in patients with COL4A1 missense mutations.These findings suggest haploinsufficiency, a different mechanism than the commonly assumed dominant-negative effect, for COL4A1 mutations as a cause of (antenatal) intracerebral hemorrhage and white matter disease.
    Human Molecular Genetics 10/2012; 22(2). DOI:10.1093/hmg/dds436 · 6.39 Impact Factor
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