ClinVar

In 3 affected members of a French Canadian family with idiopathic generalized epilepsy-13 (EIG13; 611136), Lachance-Touchette et al. (2011) identified a heterozygous 25-bp insertion close to intron 10 of the GABRA1 gene, resulting in a complex rearrangement of the transcript. RT-PCR analysis of patient cells showed that this insertion resulted in a splicing defect with retention of intron 10, a deletion of the fourth transmembrane domain, and the insertion of 18 amino acids and a premature stop codon (Lys353delins18Ter). An unaffected obligate carrier in the family also carried this mutation, which was not present in 109 healthy controls. In vitro expression studies showed that the mutant protein was retained in the endoplasmic reticulum and did not localize to the plasma membrane. Functional studies showed that the mutant subunit had no current in response to GABA, suggesting a detrimental effect on inhibitory control of neuronal circuits. The patients had late-onset afebrile, generalized tonic-clonic seizures, as well as photosensitivity.