COL4A2 mutation associated with familial porencephaly and small-vessel disease.
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.
- SourceAvailable from: Christian Johannes Gloeckner
Article: Type IV procollagen missense mutations associated with defects of the eye, vascular stability, the brain, kidney function and embryonic or postnatal viability in the mouse, Mus musculus: an extension of the Col4a1 allelic series and the identification of the first two Col4a2 mutant alleles.[show abstract] [hide abstract]
ABSTRACT: The basement membrane is important for proper tissue development, stability, and physiology. Major components of the basement membrane include laminins and type IV collagens. The type IV procollagens Col4a1 and Col4a2 form the heterotrimer [alpha1(IV)]2[alpha2(IV)], which is ubiquitously expressed in basement membranes during early developmental stages. We present the genetic, molecular, and phenotypic characterization of nine Col4a1 and three Col4a2 missense mutations recovered in random mutagenesis experiments in the mouse. Heterozygous carriers express defects in the eye, the brain, kidney function, vascular stability, and viability. Homozygotes do not survive beyond the second trimester. Ten mutations result in amino acid substitutions at nine conserved Gly sites within the collagenous domain, one mutation is in the carboxy-terminal noncollagenous domain, and one mutation is in the signal peptide sequence and is predicted to disrupt the signal peptide cleavage site. Patients with COL4A2 mutations have still not been identified. We suggest that the spontaneous intraorbital hemorrhages observed in the mouse are a clinically relevant phenotype with a relatively high predictive value to identify carriers of COL4A1 or COL4A2 mutations.Genetics 03/2007; 175(2):725-36. · 4.39 Impact Factor
Article: Mammalian collagen IV.[show abstract] [hide abstract]
ABSTRACT: Four decades have passed since the first discovery of collagen IV by Kefalides in 1966. Since then collagen IV has been investigated extensively by a large number of research laboratories around the world. Advances in molecular genetics have resulted in identification of six evolutionary related mammalian genes encoding six different polypeptide chains of collagen IV. The genes are differentially expressed during the embryonic development, providing different tissues with specific collagen IV networks each having unique biochemical properties. Newly translated alpha-chains interact and assemble in the endoplasmic reticulum in a chain-specific fashion and form unique heterotrimers. Unlike most collagens, type IV collagen is an exclusive member of the basement membranes and through a complex inter- and intramolecular interactions form supramolecular networks that influence cell adhesion, migration, and differentiation. Collagen IV is directly involved in a number of genetic and acquired disease such as Alport's and Goodpasture's syndromes. Recent discoveries have also highlighted a new and direct role for collagen IV in the development of rare genetic diseases such as cerebral hemorrhage and porencephaly in infants and hemorrhagic stroke in adults. Years of intensive investigations have resulted in a vast body of information about the structure, function, and biology of collagen IV. In this review article, we will summarize essential findings on the structural and functional relationships of different collagen IV chains and their roles in health and disease.Microscopy Research and Technique 06/2008; 71(5):357-70. · 1.59 Impact Factor
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ABSTRACT: Small-vessel diseases of the brain underlie 20 to 30 percent of ischemic strokes and a larger proportion of intracerebral hemorrhages. In this report, we show that a mutation in the mouse Col4a1 gene, encoding procollagen type IV alpha1, predisposes both newborn and adult mice to intracerebral hemorrhage. Surgical delivery of mutant mice alleviated birth-associated trauma and hemorrhage. We identified a COL4A1 mutation in a human family with small-vessel disease. We concluded that mutation of COL4A1 may cause a spectrum of cerebrovascular phenotypes and that persons with COL4A1 mutations may be predisposed to hemorrhage, especially after environmental stress.New England Journal of Medicine 05/2006; 354(14):1489-96. · 51.66 Impact Factor