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

• Published in: Journal of medical genetics Vol. 43; no. 6; pp. 490 - 495
• Main Authors: Breedveld, G, de Coo, I F, Lequin, M H, Arts, W F M, Heutink, P, Gould, D B, John, S W M, Oostra, B, Mancini, G M S
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd 01-06-2006; BMJ; BMJ Publishing Group LTD; BMJ Group
• Subjects: Adult; basement membrane; Biological and medical sciences; Brain Diseases - diagnosis; Brain Diseases - genetics; Brain Diseases - pathology; Cardiology. Vascular system; Child; Child, Preschool; COL4A1; collagen IV; Collagen Type IV - chemistry; Collagen Type IV - genetics; Collagen Type IV - physiology; Deoxyribonucleic acid; DNA; DNA Mutational Analysis; DNA polymerase; Female; General aspects. Genetic counseling; Genes; Genetic testing; Humans; Infant; Intellectual disabilities; Male; Medical genetics; Medical sciences; Middle Aged; Mutation; Mutation, Missense; NMR; Nuclear magnetic resonance; Original; Pathogenesis; Pedigree; porencephaly; Protein Structure, Tertiary; Proteins; Stroke; Thermal cycling; California; Human; Family environment; Genetics; Mutation; Hereditary; Family study
• ISSN: 0022-2593; 1468-6244; 1468-6244
• DOI: 10.1136/jmg.2005.035584

Background: Porencephaly (cystic cavities of the brain) is caused by perinatal vascular accidents from various causes. Several familial cases have been described and autosomal dominant inheritance linked to chromosome 13q has been suggested. COL4A1 is an essential component in basal membrane stability. Mouse mutants bearing an in-frame deletion of exon 40 of Col4a1 either die from haemorrhage in the perinatal period or have porencephaly in survivors. A report of inherited mutations in COL4A1 in two families has shown that familial porencephaly may have the same cause in humans. Objective: To describe three novel COL4A1 mutations. Results: The three mutations occurred in three unrelated Dutch families. There were 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 magnetic resonance imaging. Conclusions: This observation confirms COL4A1 as a major locus for genetic predisposition to perinatal cerebral haemorrhage and porencephaly and suggests variable expression of COL4A1 mutations.