Pathogenic Variants in CEP85L Cause Sporadic and Familial Posterior Predominant Lissencephaly

Area of Science:

• Genetics
• Neuroscience
• Cell Biology

Background:

• Lissencephaly (LIS) is a brain malformation characterized by a smooth brain surface due to absent cerebral convolutions.
• Genetic variants in over 20 genes cause LIS, with LIS1 (PAFAH1B1) being a major cause of posterior predominant LIS.
• A significant portion of posterior predominant LIS cases lack a known genetic cause.

Purpose of the Study:

• To identify novel genetic causes of posterior predominant LIS.
• To investigate the role of CEP85L in neuronal development and LIS pathogenesis.

Main Methods:

• Genetic analysis of individuals with posterior predominant LIS.
• Functional studies including protein localization and knockdown experiments in cell models and mice.
• Analysis of inheritance patterns in affected families.

Main Results:

• Identified rare, heterozygous CEP85L variants in 13 individuals with posterior predominant LIS.
• Demonstrated autosomal dominant inheritance in two families.
• Showed CEP85L localizes to the centrosome's pericentriolar material.
• Cep85l knockdown in mice resulted in neuronal migration defects.
• LIS1, another LIS-associated protein, also localizes to the centrosome.

Conclusions:

• CEP85L is implicated as a significant genetic cause of posterior predominant LIS.
• The centrosome plays a critical role in the pathogenesis of posterior predominant LIS.
• CEP85L variants disrupt neuronal migration, contributing to LIS development.