Novel mutations in three families confirm a major role of COL4A1 in hereditary porencephaly

Guido Breedveld ¹, Rene' F. de Coo ², Maarten H Lequin ³, Willem Frans M Arts ², Peter Heutink ⁴, Douglas B Gould ⁵, Simon W M John ⁶, Ben Oostra ⁷ and Grazia M S Mancini ^1*

¹ Departments of Clinical Genetics Erasmus University Medical Center, PO Box 1738; 3000 Rotterdam, The, Netherlands
² Child Neurology Erasmus University Medical Center, PO Box 1738; 3000 Rotterdam, The Netherlands, Netherlands
³ Radiology , Erasmus University Medical Center, PO Box 1738; 3000 Rotterdam, The Netherlands, Netherlands
⁴ Department of Human Genetics, Section of Medical Genomics, VU University Medical Center, Amsterd, Netherlands
⁵ The Howard Hughes Medical Institute and The Jackson laboratory (5), Bar Harbor, Maine, 04609, USA, United States
⁶ The Howard Hughes Medical Institute and The Jackson laboratory , Bar Harbor, Maine, 04609, USA, United States
⁷ Department of Clinical Genetics Erasmus University Medical Center, PO Box 1738; 3000 Rotterdam, The, Netherlands

^* To whom correspondence should be addressed. E-mail: g.mancini{at}erasmusmc.nl.

Accepted 10 August 2005

Abstract

Introduction: Porencephaly (cystic cavities of the brain) is caused by perinatal vascular accidents of different cause. Several familial cases have been described and autosomal dominant inheritance, linked to chromosome 13q has been suggested. COL4A1 is an essential component for basal membrane stability.

Methods: Mouse mutants bearing an in-frame deletion of exon 40 of Col4a1 show perinatal death with hemorrhage and porencephaly in survivors. Report of inherited mutations in COL4A1 in two families has demonstrated that familial porencephaly may have the same cause in humans.

Results: We report three novel COL4A1 mutations in three unrelated Dutch families, two missense mutations of glycine residues predicted to result in abnormal collagen IV assembly and one mutation predicted to abolish the traditional COL4A1 start codon. The last mutation was also present in an asymptomatic obligate carrier with white matter abnormalities on brain MRI.

Discussion: Our observation confirms COL4A1 as a major locus for genetic predisposition to perinatal cerebral hemorrhage and porencephaly and suggests variable expression of COL4A1 mutations.

Keywords: COL4A1, basement membrane, collagen IV, porencephaly, stroke

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