MICAL1 and Epilepsy

MICAL1 encodes a monooxygenase involved in semaphorin signaling and actin cytoskeletal regulation. A single patient with benign childhood epilepsy with centrotemporal spikes harbored a heterozygous c.-43-1G>A splice‐region variant that disrupted 5′UTR structure and produced two aberrant transcripts in minigene assays (PMID:38705457). The variant was inherited from an unaffected mother, indicating incomplete penetrance; no additional segregating affected relatives have been reported. Therefore, current genetic evidence is limited to a single family.

Functional data from autosomal dominant lateral temporal epilepsy suggest that activating MICAL1 mutations, including p.Gly150Ser, increase enzymatic activity and induce cytoskeletal alterations that could impair axonal guidance (PMID:35627100). These findings provide moderate support for a gain-of-function mechanism in epilepsy. However, the paucity of unrelated probands and lack of robust segregation preclude a definitive classification. Additional case reports, segregation analyses, and in vivo models are warranted. Key take-home: MICAL1 variants are candidate risk factors for epilepsy with autosomal dominant inheritance and incomplete penetrance, meriting further study.

References

• European journal of medical genetics • 2024 • A novel splicing variant in MICAL-1 gene is associated with epilepsy. PMID:38705457
• Genes • 2022 • MICAL1 Monooxygenase in Autosomal Dominant Lateral Temporal Epilepsy: Role in Cytoskeletal Regulation and Relation to Cancer. PMID:35627100

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