Mutations in MICAL-1cause autosomal-dominant lateral temporal epilepsy

Area of Science:

• Neurogenetics
• Molecular biology
• Epilepsy research

Background:

• Autosomal-dominant lateral temporal epilepsy (ADLTE) is a genetic focal epilepsy often presenting with auditory symptoms.
• While LGI1 and RELN genes are implicated, the genetic basis for approximately half of ADLTE cases remains unknown.
• Understanding the molecular mechanisms underlying ADLTE is crucial for developing targeted therapies.

Purpose of the Study:

• To identify novel genes responsible for ADLTE in genetically unsolved families.
• To elucidate the molecular pathways contributing to the pathogenesis of ADLTE.

Main Methods:

• Whole exome sequencing and genome-wide single-nucleotide polymorphism-array linkage analysis were performed on Italian ADLTE families.
• Segregation analysis was conducted to confirm the pathogenicity of identified variants.
• Cell-based assays were used to assess the functional impact of MICAL-1 variants.

Main Results:

• Two pathogenic variants in the MICAL-1 gene were identified in separate ADLTE families: a missense variant (p.Gly150Ser) in the monooxygenase domain and a frameshift variant (p.Ala1065fs) in the C-terminal domain.
• Both MICAL-1 variants significantly increased the gene's oxidoreductase activity and induced cell contraction, linked to F-actin dynamics deregulation.
• No other candidate gene variants were found to be implicated in ADLTE within the studied cohort.

Conclusions:

• Pathogenic variants in MICAL-1 represent a novel genetic cause of ADLTE.
• Dysregulation of actin cytoskeleton dynamics due to altered MICAL-1 activity is a proposed mechanism underlying ADLTE.
• This study expands the genetic landscape of ADLTE and highlights the role of MICAL-1 in neuronal function and epilepsy.