title: Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly.
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.
authors.affiliation: Howard Hughes Medical Institute, Bar Harbor, ME 04609, USA.
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Gould
authors.forename: F Campbell
authors.initials: FC
authors.lastname: Phalan
authors.forename: Guido J
authors.initials: GJ
authors.lastname: Breedveld
authors.forename: Saskia E
authors.initials: SE
authors.lastname: van Mil
authors.forename: Richard S
authors.initials: RS
authors.lastname: Smith
authors.forename: John C
authors.initials: JC
authors.lastname: Schimenti
authors.forename: Umberto
authors.initials: U
authors.lastname: Aguglia
authors.forename: Marjo S
authors.initials: MS
authors.lastname: van der Knaap
authors.forename: Peter
authors.initials: P
authors.lastname: Heutink
authors.forename: Simon W M
authors.initials: SW
authors.lastname: John
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D000831:Animals, Newborn; D001485:Basement Membrane / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000098:blood supply / Q000196:embryology / Q000473:pathology*; D001927:Brain Diseases / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D002543:Cerebral Hemorrhage / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D002874:Chromosome Mapping; D024141:Collagen Type IV / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D004707:Endoderm / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D051379:Mice; D009154:Mutation; D017434:Protein Structure, Tertiary
chemical_list: C000619517:Col4a1 protein, mouse; D024141:Collagen Type IV