Deleterious Rare Variants Reveal Risk for Loss of GABAA Receptor Function in Patients with Genetic Epilepsy and in the General Population.
Genetic epilepsies (GEs) account for approximately 50% of all seizure disorders, and familial forms include mutations in single GABAA receptor subunit genes (GABRs). In 144 sporadic GE cases (GECs), exome sequencing of 237 ion channel genes identified 520 GABR variants. Among these variants, 33 rare variants in 11 GABR genes were present in 24 GECs. To assess functional risk of variants in GECs, we selected 8 variants found in GABRA, 3 in GABRB, and 3 in GABRG and compared them to 18 variants found in the general population for GABRA1 (n = 9), GABRB3 (n = 7), and GABRG2 (n = 2). To identify deleterious variants and gain insight into structure-function relationships, we studied the gating properties, surface expression and structural perturbations of the 32 variants. Significant reduction of GABAA receptor function was strongly associated with variants scored as deleterious and mapped within the N-terminal and transmembrane domains. In addition, 12 out of 17 variants mapped along the β+/α- GABA binding interface, were associated with reduction in channel gating and were predicted to cause structural rearrangements of the receptor by in silico simulations. Missense or nonsense mutations of GABRA1, GABRB3 and GABRG2 primarily impair subunit biogenesis. In contrast, GABR variants affected receptor function by impairing gating, suggesting that different mechanisms are operating in GABR epilepsy susceptibility variants and disease-causing mutations. The functional impact of single GABR variants found in individuals with sporadic GEs warrants the use of molecular diagnosis and will ultimately improve the treatment of genetic epilepsies by using a personalized approach.
Department of Neurology, Vanderbilt University, Nashville, Tennessee, 37232, United States of America.
Ciria C
CC
Hernandez
Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, V6S 1Z3, Canada.
Tara L
TL
Klassen
Program in Neuroscience, Vanderbilt University, Nashville, Tennessee, 37232, United States of America.
Laurel G
LG
Jackson
Program in Neuroscience, Vanderbilt University, Nashville, Tennessee, 37232, United States of America.
Katharine
K
Gurba
Department of Neurology, Vanderbilt University, Nashville, Tennessee, 37232, United States of America.
Ningning
N
Hu
Department of Neurology, Baylor College of Medicine, Houston, Texas, 77030, United States of America.
Jeffrey L
http://orcid.org/0000-0002-2887-0839
JL
Noebels
Department of Neurology, Vanderbilt University, Nashville, Tennessee, 37232, United States of America.
Robert L
RL
Macdonald
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D016022:Case-Control Studies; D004827:Epilepsy / Q000235:genetics* / Q000378:metabolism*; D014644:Genetic Variation; D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating / Q000235:genetics; D008958:Models, Molecular; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D009154:Mutation; D020125:Mutation, Missense; D000072417:Protein Domains; D021122:Protein Subunits / Q000737:chemistry / Q000235:genetics; D011963:Receptors, GABA-A / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
D050505:Mutant Proteins; D021122:Protein Subunits; D011963:Receptors, GABA-A; D011994:Recombinant Proteins