title: COL4A2 mutation associated with familial porencephaly and small-vessel disease.
abstract: Familial porencephaly, leukoencephalopathy and small-vessel disease belong to the spectrum of disorders ascribed to dominant mutations in the gene encoding for type IV collagen alpha-1 (COL4A1). Mice harbouring mutations in either Col4a1 or Col4a2 suffer from porencephaly, hydrocephalus, cerebral and ocular bleeding and developmental defects. We observed porencephaly and white matter lesions in members from two families that lack COL4A1 mutations. We hypothesized that COL4A2 mutations confer genetic predisposition to porencephaly, therefore we sequenced COL4A2 in the family members and characterized clinical, neuroradiological and biochemical phenotypes. Genomic sequencing of COL4A2 identified the heterozygous missense G1389R in exon 44 in one family and the c.3206delC change in exon 34 leading to frame shift and premature stop, in the second family. Fragmentation and duplication of epidermal basement membranes were observed by electron microscopy in a c.3206delC patient skin biopsy, consistent with abnormal collagen IV network. Collagen chain accumulation and endoplasmic reticulum (ER) stress have been proposed as cellular mechanism in COL4A1 mutations. In COL4A2 (3206delC) fibroblasts we detected increased rates of apoptosis and no signs of ER stress. Mutation phenotypes varied, including porencephaly, white matter lesions, cerebellar and optic nerve hypoplasia and unruptured carotid aneurysm. In the second family however, we found evidence for additional factors contributing to the phenotype. We conclude that dominant COL4A2 mutations are a novel major risk factor for familial cerebrovascular disease, including porencephaly and small-vessel disease with reduced penetrance and variable phenotype, which might also be modified by other contributing factors.
authors.affiliation: Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Elly
authors.initials: E
authors.lastname: Verbeek
authors.forename: Marije E C
authors.initials: ME
authors.lastname: Meuwissen
authors.forename: Frans W
authors.initials: FW
authors.lastname: Verheijen
authors.forename: Paul P
authors.initials: PP
authors.lastname: Govaert
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Licht
authors.forename: Debbie S
authors.initials: DS
authors.lastname: Kuo
authors.forename: Cathryn J
authors.initials: CJ
authors.lastname: Poulton
authors.forename: Rachel
authors.initials: R
authors.lastname: Schot
authors.forename: Maarten H
authors.initials: MH
authors.lastname: Lequin
authors.forename: Jeroen
authors.initials: J
authors.lastname: Dudink
authors.forename: Dicky J
authors.initials: DJ
authors.lastname: Halley
authors.forename: René I F
authors.initials: RI
authors.lastname: de Coo
authors.forename: Jan C
authors.initials: JC
authors.lastname: den Hollander
authors.forename: Renske
authors.initials: R
authors.lastname: Oegema
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Gould
authors.forename: Grazia M S
authors.initials: GM
authors.lastname: Mancini
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001483:Base Sequence; D001485:Basement Membrane / Q000473:pathology / Q000648:ultrastructure; D001921:Brain / Q000473:pathology; D001927:Brain Diseases / Q000175:diagnosis / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D024141:Collagen Type IV / Q000172:deficiency / Q000235:genetics*; D003241:Consanguinity; D059865:Endoplasmic Reticulum Stress; D005091:Exons; D005260:Female; D020022:Genetic Predisposition to Disease; D006429:Hemiplegia / Q000175:diagnosis / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007223:Infant; D002532:Intracranial Aneurysm / Q000175:diagnosis / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D010375:Pedigree; D065708:Porencephaly; D012867:Skin / Q000473:pathology / Q000648:ultrastructure; D055815:Young Adult
chemical_list: C502625:COL4A2 protein, human; D024141:Collagen Type IV