1. Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly.
- Author
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Gould DB, Phalan FC, Breedveld GJ, van Mil SE, Smith RS, Schimenti JC, Aguglia U, van der Knaap MS, Heutink P, and John SW
- Subjects
- Alleles, Amino Acid Sequence, Amino Acid Substitution, Animals, Animals, Newborn, Basement Membrane embryology, Basement Membrane metabolism, Basement Membrane pathology, Brain blood supply, Brain embryology, Brain Diseases etiology, Brain Diseases pathology, Cerebral Hemorrhage etiology, Cerebral Hemorrhage pathology, Chromosome Mapping, Collagen Type IV chemistry, Collagen Type IV metabolism, Endoderm metabolism, Heterozygote, Humans, Mice, Protein Structure, Tertiary, Brain pathology, Brain Diseases genetics, Cerebral Hemorrhage genetics, Collagen Type IV genetics, Mutation
- Abstract
Porencephaly is a rare neurological disease, typically manifest in infants, which is characterized by the existence of degenerative cavities in the brain. To investigate the molecular pathogenesis of porencephaly, we studied a mouse mutant that develops porencephaly secondary to focal disruptions of vascular basement membranes. Half of the mutant mice died with cerebral hemorrhage within a day of birth, and approximately 18% of survivors had porencephaly. We show that vascular defects are caused by a semidominant mutation in the procollagen type IV alpha 1 gene (Col4a1) in mice, which inhibits the secretion of mutant and normal type IV collagen. We also show that COL4A1 mutations segregate with porencephaly in human families. Because not all mutant mice develop porencephaly, we propose that Col4a1 mutations conspire with environmental trauma in causing the disease.
- Published
- 2005
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