Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly.
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.
Gould
Douglas B
DB
Howard Hughes Medical Institute, Bar Harbor, ME 04609, USA.
Phalan
F Campbell
FC
Breedveld
Guido J
GJ
van Mil
Saskia E
SE
Smith
Richard S
RS
Schimenti
John C
JC
Aguglia
Umberto
U
van der Knaap
Marjo S
MS
Heutink
Peter
P
John
Simon W M
SW
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
C000619517:Col4a1 protein, mouse; D024141:Collagen Type IV