Mutations in LAMB1 cause cobblestone brain malformation without muscular or ocular abnormalities

Am J Hum Genet. 2013 Mar 7;92(3):468-74. doi: 10.1016/j.ajhg.2013.02.005.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Basement Membrane / metabolism
  • Basement Membrane / pathology
  • Brain / abnormalities*
  • Brain / metabolism
  • Brain / pathology
  • Cerebellum / metabolism
  • Cerebellum / pathology
  • Cerebral Cortex / metabolism
  • Cerebral Cortex / pathology
  • Encephalocele / genetics
  • Encephalocele / metabolism
  • Encephalocele / pathology
  • Female
  • Genetic Predisposition to Disease
  • Homozygote
  • Humans
  • Laminin / genetics*
  • Male
  • Muscular Dystrophies / genetics*
  • Muscular Dystrophies / metabolism
  • Muscular Dystrophies / pathology
  • Nervous System Malformations / genetics*
  • Nervous System Malformations / metabolism
  • Nervous System Malformations / pathology
  • Neuroglia / metabolism
  • Neuroglia / pathology
  • Neurons / metabolism
  • Neurons / pathology
  • Sequence Deletion*
  • Walker-Warburg Syndrome / genetics*
  • Walker-Warburg Syndrome / metabolism
  • Walker-Warburg Syndrome / pathology

Substances

  • LAMB1 protein, human
  • Laminin