Title

Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly.

Document Type

Article

Publication Date

2005

Keywords

Amino-Acid-Sequence, Amino-Acid-Substitution, Animals, Animals-Newborn, Basement-Membrane, Brain, Brain-Diseases, Cerebral-Hemorrhage, Chromosome-Mapping, Collagen-Type-IV, Endoderm, Heterozygote, Humans, Mice, Mutation, Protein-Structure-Tertiary

JAX Source

Science 2005 May; 308(5725):1167-71.

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.