TABLE 4.
Summary of GABA-A receptor genetic epilepsies
The positions of mutations are designated in the immature peptide including the 39 amino acid signal peptide.
| Genetic Location | Mutation | Sample Size | Receptor Dysfunction | Phenotype OMIM# | |
|---|---|---|---|---|---|
| CAE | |||||
| α1 (GABRA1) | 5q34 | (975delC, S326fs328X) A single bp deletion and premature stop codon in TM3 | Sporadic 1 of 98 German patients with IGE | Reduced GABA current and surface expression (Maljevic et al., 2006) | 611136 |
| α6 (GABRA6) | 5q34 | (R46W) A missense mutation in N terminus, causing the changes of arginine to tryptophan at position 46 | 1 of 72 patients with IGE, 65 patients with GEFS+, 66 patients with FS | Impaired receptor assembly/trafficking; reduced surface expression of δ subunit (Dibbens et al., 2009; Hernandez et al., 2011) | |
| β3 (GABRB3) | 15q12 | Haplotype 2 promoter in exon 1a | 45 patients with CAE | Lower transcription activity (Feucht et al., 1999; Urak et al., 2006) | 612269 |
| (P11S) A heterozygous missense mutation in exon 1a in signal peptide, causing the changes of proline to serine at position 11 | 4 of 48 patients with remitting CAE in a Mexican family | Reduced GABA current and increased glycosylation (Tanaka et al., 2008) | |||
| (S15F) A missense mutation in signal peptide, causing the changes of serine to phenylalanine at position 15 | 1 of 48 patients with remitting CAE from Honduras | Reduced GABA current and increased glycosylation (Tanaka et al., 2008) | |||
| (G32R) A missense mutation in exon 2 in N terminus, causing the changes of glycine to arginine at position 32) | 2 of 48 patients with remitting CAE in a Honduran family | Reduced GABA current and increased glycosylation (Tanaka et al., 2008) | |||
| γ2 (GABRG2) | 5q34 | (R82Q) A missense mutation in N terminus, causing the changes of arginine to glutamine at position 82 | Autosomal dominant form in a large Australian family | Impaired receptor trafficking and reduced surface expression (Wallace et al., 2001) | 607681 |
| JME | |||||
| α1 (GABRA1) | 5q34 | (A332D) A heterozygous missense mutation in TM3, causing the changes of alanine to aspartate at position 322 | 14 members of a French Canadian family | Reduced GABA current and surface expression (Cossette et al., 2002) | 611136 |
| δ (GABRD) | 1p36.3 | (R220H) A missense mutation in exon 6 in N terminus, causing the changes of arginine to histidine at position 220 | A small GEFS+ family | Reduced surface expression and receptor mean open duration (Dibbens et al., 2004) | 613060 |
| FS | |||||
| γ2 (GABRG2) | 5q34 | (R82Q) A missense mutation in N terminus, causing the changes of arginine to glutamine at position 82 | Autosomal dominant form in a large Australian family | Impaired receptor trafficking and reduced surface expression (Wallace et al., 2001) | 611277 |
| (R177G) A missense mutation in N terminus, causing the changes of arginine to glycine at position 177 | 1 of 47 unrelated patients | Altered GABA current and kinetics and impaired subunit folding and/or oligomerization(Audenaert et al., 2006) | |||
| (K328M) A missense mutation in extracellular loop between the TM2 and TM3, causing the changes of lysine to methionine at position 328 | A large French family | Altered GABA current and kinetics (Baulac et al., 2001) | |||
| GEFS+ | |||||
| γ2 (GABRG2) | 5q34 | (K328M) A missense mutation in extracellular loop between the TM2 and TM3, causing the changes of lysine to methionine at position 328 | A large French family with GEFS+ | Altered GABA current and kinetics (Baulac et al., 2001) | 611277 |
| (Q390X) A nonsense mutation in intracellular loop between the TM3 and TM4, causing a premature stop codon at position 390 | A GEFS+ family | ER retention and abolished GABA sensitivity (Harkin et al., 2002; Kang et al., 2010) | |||
| (R136X) A nonsense mutation in N terminus, causing a premature stop codon at position 136 | A two-generation family with GEFS+ | Reduced receptor current amplitudes and surface expression, ER retention (Sun et al., 2008; Johnston et al., 2014) | |||
| (W429X) A nonsense mutation in intracellular loop between the TM3 and TM4, causing a premature stop codon at position 429 | 1 of 23 Chinese families with GEFS+ | Undetermined, is predicted to translate a truncated protein (Sun et al., 2008; Johnston et al., 2014) | |||
| δ (GABRD) | 1p36.3 | (R220C) A missense mutation in exon 6 in N terminus, causing the changes of arginine to cysteine at position 220 | A small GEFS+ family | Reduced GABA current and single channel open duration (Dibbens et al., 2004) | 613060 |
| (E177A) A missense mutation in N terminus, causing the changes of glutamate to alanine at position 177 | A small GEFS+ family | Reduced GABA current and receptor expression and altered channel gating frequency (Dibbens et al., 2004) | |||
| DS | |||||
| γ2 (GABRG2) | 5q34 | (Q40X) A nonsense mutation in N terminus, causing a premature stop codon at position 40 | Dizygotic twin girls with DS and their apparently healthy father in a Japanese family | Haploinsufficiency and abnormal intracellular trafficking (Hirose 2006; Ishii et al., 2014) | |
OMIM, Online Mendelian Inheritance in Man, a daily updated catalog of human genes and genetic disorders.