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Mutations in LAMB1 cause cobblestone brain malformation without muscular or ocular abnormalities
Farid Radmanesh1, Ahmet Okay Caglayan, Jennifer L Silhavy
1Neurogenetics Laboratory, Department of Neurosciences, University of California, San Diego, CA 92093, USA.
Cobblestone brain malformation, a neuronal migration disorder, is linked to mutations in LAMB1. This gene defect disrupts brain development, causing malformations and affecting radial glial cell connections.
Area of Science:
- Neuroscience
- Genetics
- Developmental Biology
Background:
- Cobblestone brain malformation (COB) is a rare neuronal migration disorder.
- It is often associated with dystroglycanopathy congenital muscular dystrophies and muscle-eye-brain disease.
Purpose of the Study:
- To identify the genetic cause of autosomal-recessive COB in two families.
- To investigate the role of LAMB1 in brain development and COB pathogenesis.
Main Methods:
- Genetic analysis of affected individuals from two families.
- Clinical evaluation of brain, ocular, and muscular abnormalities.
Main Results:
- Identified homozygous deleterious mutations in LAMB1 (encoding laminin subunit beta-1).
- Affected individuals presented with brain malformations (cortical, white matter, cerebellar, brainstem, encephalocele) but milder ocular/muscular issues.
- LAMB1's localization to the pial basement membrane was confirmed.
Conclusions:
- Homozygous LAMB1 mutations cause a distinct form of cobblestone brain malformation.
- Defective LAMB1-mediated connection between radial glial cells and the pial surface underlies this malformation.
- This finding expands the spectrum of LAMB1-related disorders.
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