Variants in LAMC3 Causes Occipital Cortical Malformation

Area of Science:

• Genetics
• Neuroscience
• Developmental Biology

Background:

• Occipital cortical malformation (OCCM) is a developmental brain disorder characterized by occipital lobe polymicrogyria/pachygyria and early-onset seizures.
• Recessive or complex heterozygous variants in the LAMC3 gene are known causes of OCCM.

Purpose of the Study:

• To identify novel genetic variants associated with OCCM.
• To investigate the functional consequences of identified variants in a patient with childhood-onset seizures and normal cranial MRI.

Main Methods:

• Genetic analysis to identify LAMC3 variants.
• Functional experiments to assess the impact of variants on laminin γ3 chain.
• Bioinformatics analysis for gene interactions and pathway enrichment (KEGG).

Main Results:

• Novel complex heterozygous variants (c.470G > A and c.4030 + 1G > A) in the LAMC3 gene were identified in a Chinese female patient.
• Functional studies confirmed these variants lead to premature truncation of the laminin γ3 chain.
• Bioinformatics analysis revealed interactions with genes involved in basement membrane and extracellular matrix, implicating ECM receptor interaction and PI3K-Akt signaling pathways in OCCM pathogenesis.

Conclusions:

• The identified LAMC3 variants are likely causative of OCCM in this patient.
• Laminin γ3 chain dysfunction, through altered extracellular matrix interactions and signaling pathways, contributes to OCCM development.