EFHC1 – Juvenile Myoclonic Epilepsy

EFHC1 encodes a calcium-binding microtubule-associated protein implicated in neuronal migration and spindle organization. Heterozygous mutations in EFHC1 cause autosomal dominant juvenile myoclonic epilepsy (MONDO:0009696). Initial linkage to the EJM1 locus on chromosome 6p12-p11 led to the discovery of pathogenic EFHC1 variants disrupting R-type calcium currents and neuronal architecture.

Genetic evidence stems from identification of five missense mutations in six unrelated families with JME that cosegregated with disease and were absent in 382 controls (PMID:15258581). An Italian series confirmed EFHC1 mutations (including c.687T>G (p.Phe229Leu)) cosegregating in three additional families (PMID:17634063). These studies define an autosomal dominant inheritance with segregation across 9 affected relatives.

Rare EFHC1 variants have been reported across diverse populations, including Turkish, Indian, and Hispanic cohorts, with allele frequencies modulated by ancestry (PMID:38088014; PMID:29750216). However, EFHC1 mutations are tolerated in some healthy individuals, highlighting incomplete penetrance and genetic background effects (PMID:25489633). A Dutch linkage cohort showed no EFHC1 mutations, supporting locus heterogeneity (PMID:17054699).

Functional assays demonstrate that JME-associated EFHC1 variants act dominantly to impair mitotic spindle organization and neuronal migration in cultured neurons (PMID:22926142). EFHC1 potentiates TRPM2-mediated Ca2+ currents and cell death in HEK293 cells, effects reversed by JME mutations (PMID:22226147). In Drosophila, Defhc1.1 knockout yields neuromuscular junction overgrowth and increased neurotransmitter release, recapitulating microtubule defects (PMID:21835885).

Despite some variants found in healthy controls and variable detection rates across ethnicities, convergent mechanistic data support a dominant-negative gain-of-function model. Additional large cohorts and functional studies have not been scored here due to scope. Key take-home: EFHC1 mutation testing aids diagnosis of JME but must consider incomplete penetrance and population-specific allele frequencies.

References

• Nature Genetics • 2004 • Mutations in EFHC1 cause juvenile myoclonic epilepsy. PMID:15258581
• Human Molecular Genetics • 2012 • Mutations of EFHC1, linked to juvenile myoclonic epilepsy, disrupt radial and tangential migrations during brain development. PMID:22926142
• Cell Calcium • 2012 • The juvenile myoclonic epilepsy-related protein EFHC1 interacts with the redox-sensitive TRPM2 channel linked to cell death. PMID:22226147
• Human Molecular Genetics • 2011 • Defhc1.1, a homologue of the juvenile myoclonic gene EFHC1, modulates architecture and basal activity of the neuromuscular junction in Drosophila. PMID:21835885
• Neurology • 1997 • Refined mapping of the epilepsy susceptibility locus EJM1 on chromosome 6. PMID:9305351
• Epilepsia • 2006 • Heterogeneity at the JME 6p11-12 locus: absence of mutations in the EFHC1 gene in linked Dutch families. PMID:17054699

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