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Science 20 May 2005:
Vol. 308. no. 5725, pp. 1167 - 1171
DOI: 10.1126/science.1109418
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Reports

Mutations in Col4a1 Cause Perinatal Cerebral Hemorrhage and Porencephaly

Douglas B. Gould,1,2 F. Campbell Phalan,1,2 Guido J. Breedveld,3 Saskia E. van Mil,4 Richard S. Smith,1,2 John C. Schimenti,2* Umberto Aguglia,5 Marjo S. van der Knaap,6 Peter Heutink,4 Simon W. M. John1,2,7{dagger}

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 ~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.

1 The Howard Hughes Medical Institute, Bar Harbor, ME 04609, USA.
2 The Jackson Laboratory, 600 Maine Street, Bar Harbor, ME 04609 USA.
3 Department of Clinical Genetics, Erasmus Medical Center, 3000 DR, Rotterdam, Netherlands.
4 Department of Human Genetics, Section of Medical Genomics, VU University Medical Center, and Center for Neurogenomics and Cognitive Research, VU University and VU University Medical Center, 1081 BT, Amsterdam, Netherlands.
5 Regional Epilepsy Center, University of Catanzaro, 89100, Reggio Calabria, Italy.
6 Department of Child Neurology, VU University Medical Center, 1081 BT, Amsterdam, Netherlands.
7 Department of Ophthalmology, Tufts University School of Medicine, Boston, MA 02111, USA.

* Present address: Department of Biomedical Sciences, Cornell University, Ithaca, NY, 14853, USA.

{dagger} To whom correspondence should be addressed. E-mail: swmj{at}jax.org

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