Neurobiology of Disease Subunit Susceptibility Variants E177A and R220H Associated with Complex Epilepsy Alter Channel Gating and Surface Expression of 4 2 GABAA Receptors
نویسندگان
چکیده
Hua-Jun Feng,1 Jing-Qiong Kang,1 Luyan Song,1 Leanne Dibbens,4,5 John Mulley,4,6 and Robert L. Macdonald1,2,3 Departments of 1Neurology, 2Molecular Physiology and Biophysics, and 3Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37212, 4Department of Genetic Medicine, Women’s and Children’s Hospital, 5Department of Pediatrics, and 6School of Molecular and Biomedical Sciences, The University of Adelaide, Adelaide, SA 5031, Australia
منابع مشابه
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...
متن کاملGABRD encoding a protein for extra- or peri-synaptic GABAA receptors is a susceptibility locus for generalized epilepsies.
A major challenge in understanding complex idiopathic generalized epilepsies has been the characterization of their underlying molecular genetic basis. Here, we report that genetic variation within the GABRD gene, which encodes the GABAA receptor delta subunit, affects GABA current amplitude consistent with a model of polygenic susceptibility to epilepsy in humans. We have found a GABRD Glu177A...
متن کاملAltered Channel Conductance States and Gating of GABAA Receptors by a Pore Mutation Linked to Dravet Syndrome
We identified a de novo missense mutation, P302L, in the γ-aminobutyric acid type A (GABAA) receptor γ2 subunit gene GABRG2 in a patient with Dravet syndrome using targeted next-generation sequencing. The mutation was in the cytoplasmic portion of the transmembrane segment M2 of the γ2 subunit that faces the pore lumen. GABAA receptor α1 and β3 subunits were coexpressed with wild-type (wt) γ2L ...
متن کاملBrief Communication The GABAA Receptor 2 Subunit R43Q Mutation Linked to Childhood Absence Epilepsy and Febrile Seizures Causes Retention of 1 2 2S Receptors in the Endoplasmic Reticulum
The GABAA receptor 2 subunit mutation R43Q is an autosomal dominant mutation associated with childhood absence epilepsy and febrile seizures. Previously, we demonstrated that homozygous 1 3 2L(R43Q) receptor whole-cell currents had reduced amplitude with unaltered time course, suggesting reduced cell surface expression of functional receptors. In human embryonic kidney 293-T cells, we demonstra...
متن کاملQuantitative Analysis of GABAA Gamma Receptor Subunits in the Developing Embryonic Chick Forebrain
Objective(s) In this study we investigated the expression of GABAA receptor subunits during brain development. These receptors may change in the embryonic chick forebrain. Materials and Methodes The expression levels of four types of GABAA receptor gamma subunits (γ1, γ2, γ3 and γ4) were quantified in the embryonic chick forebrain at 32 hr, 3, 7, 14, and 20 days of incubation and day one aft...
متن کامل