title: Mutations in LAMB1 cause cobblestone brain malformation without muscular or ocular abnormalities.
abstract: Cobblestone brain malformation (COB) is a neuronal migration disorder characterized by protrusions of neurons beyond the first cortical layer at the pial surface of the brain. It is usually seen in association with dystroglycanopathy types of congenital muscular dystrophies (CMDs) and ocular abnormalities termed muscle-eye-brain disease. Here we report homozygous deleterious mutations in LAMB1, encoding laminin subunit beta-1, in two families with autosomal-recessive COB. Affected individuals displayed a constellation of brain malformations including cortical gyral and white-matter signal abnormalities, severe cerebellar dysplasia, brainstem hypoplasia, and occipital encephalocele, but they had less apparent ocular or muscular abnormalities than are typically observed in COB. LAMB1 is localized to the pial basement membrane, suggesting that defective connection between radial glial cells and the pial surface mediated by LAMB1 leads to this malformation.
authors.affiliation: Neurogenetics Laboratory, Department of Neurosciences, University of California, San Diego, CA 92093, USA.
authors.forename: Farid
authors.initials: F
authors.lastname: Radmanesh
authors.forename: Ahmet Okay
authors.initials: AO
authors.lastname: Caglayan
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Silhavy
authors.forename: Cahide
authors.initials: C
authors.lastname: Yilmaz
authors.forename: Vincent
authors.initials: V
authors.lastname: Cantagrel
authors.forename: Tarek
authors.initials: T
authors.lastname: Omar
authors.forename: Başak
authors.initials: B
authors.lastname: Rosti
authors.forename: Hande
authors.initials: H
authors.lastname: Kaymakcalan
authors.forename: Stacey
authors.initials: S
authors.lastname: Gabriel
authors.forename: Mingfeng
authors.initials: M
authors.lastname: Li
authors.forename: Nenad
authors.initials: N
authors.lastname: Sestan
authors.forename: Kaya
authors.initials: K
authors.lastname: Bilguvar
authors.forename: William B
authors.initials: WB
authors.lastname: Dobyns
authors.forename: Maha S
authors.initials: MS
authors.lastname: Zaki
authors.forename: Murat
authors.initials: M
authors.lastname: Gunel
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Gleeson
mesh_terms: D001485:Basement Membrane / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000002:abnormalities* / Q000378:metabolism / Q000473:pathology; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D004677:Encephalocele / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D020022:Genetic Predisposition to Disease; D006720:Homozygote; D006801:Humans; D007797:Laminin / Q000235:genetics*; D008297:Male; D009136:Muscular Dystrophies / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009421:Nervous System Malformations / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D017384:Sequence Deletion; D058494:Walker-Warburg Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: C478221:LAMB1 protein, human; D007797:Laminin