GABRA1 – Juvenile Myoclonic Epilepsy

Heterozygous missense variants in GABRA1 have been implicated in autosomal dominant juvenile myoclonic epilepsy (JME). A c.965C>A (p.Ala322Asp) substitution co-segregated with JME in a large French Canadian pedigree, with at least eight affected relatives demonstrating autosomal dominant inheritance (PMID:11992121). Subsequent screening of 35 unrelated JME families from India failed to identify p.Ala322Asp, suggesting locus heterogeneity or population specificity (PMID:14631097). More recently, two additional JME probands harboring distinct GABRA1 missense changes, including c.220G>A (p.Val74Ile), were reported among 16 novel cases with idiopathic generalized epilepsy (PMID:27521439).

Functional analyses in Xenopus oocytes have shown that receptors incorporating p.Ala322Asp or other GABRA1 variants exhibit significantly reduced GABA-activated currents, consistent with a loss-of-function mechanism (PMID:11992121; PMID:27521439). These data support a model of haploinsufficiency of the GABA(A) α1 subunit leading to cortical hyperexcitability. Despite limited replication across diverse populations, GABRA1 testing can guide diagnosis and cascade screening in families with JME. Key take-home: GABRA1 missense variants confer a loss-of-function predisposition to autosomal dominant JME, warranting their inclusion in epilepsy gene panels for diagnostic decision-making.

References

• Nature Genetics • 2002 • Mutation of GABRA1 in an autosomal dominant form of juvenile myoclonic epilepsy PMID:11992121
• Journal of Genetics • 2003 • Absence of GABRA1 Ala322Asp mutation in juvenile myoclonic epilepsy families from India PMID:14631097
• Neurology • 2016 • Phenotypic spectrum of GABRA1: From generalized epilepsies to severe epileptic encephalopathies PMID:27521439

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