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.
Bibliographical noteFunding Information:
We are grateful to the families for their participation in the study. We thank the Broad Institute (supported by the US National Human Genome Research Institute; grant U54HG003067 to E. Lander), the Yale Center for Mendelian Disorders; (grant U54HG006504 to R. Lifton, M. Gunel, M. Gerstein, and S. Mane) for sequencing support and analysis, J. Santini at the UCSD Microscopy Core for imaging (P30NS047101), the Yale Biomedical High Performance Computing Center for data analysis and storage, the Yale Program on Neurogenetics, the Yale Center for Human Genetics and Genomics, and Carsten G. Bönnemann (National Institute of Neurological Disorders and Stroke) for discussions. This work was supported by US National Institutes of Health (NIH) grant RC2NS070477 and the Gregory M. Kiez and Mehmet Kutman Foundation (M.G.), NIH grants U01MH081896 (to N.Š.), R01NS048453, R01NS052455, and P01HD070494, the Simons Foundation Autism Research Initiative, and the Howard Hughes Medical Institute (to J.G.G.).