[SP6-3D-1] De novo mutations of GRIA3 in two children with epilepsy and intellectual/developmental disabilities
Glutamate ionotropic AMPA receptors (iGluRs) are major components in the mediation of excitatory synaptic transmission in the CNS. iGluRs are essential for the induction and maintenance of long-term potentiation and long-term depression associated with learning, memory and several neurological developmental disorders. GRIA3, encoding AMPA receptor type subunit 3(iGluR3), was reported associated with x-linked mental retardation. iGluR3 is composed by two ligand-binding domains (S1 and S2) and 4 transmembrane domains (TM1-4).
Targeted next-generation sequencing was performed in Chinese children with epilepsy of unknown etiology and intellectual/developmental disabilities (IDDs). Two novel de novo hemizygous missense mutations in GRIA3 (NM_000828: c.1957G>T, p. Ala653Ser and NM_000828: c.1973T>C, p. Val658Ala) was identified, confirmed by Sanger sequencing and predicted as disease causing by Polyphen-2, SIFT, Mutation taster and Align-GVGD. Two mutations are both located at the ligand-binding domain S2, nearing the binding site of glutamate. The two patients were both male. They presented with focal seizures with generalization during sleep before 2yrs old and status epilepticus in the next few years. Brain MRI, metabolic workup and physical examinations were unremarkable. Patient with c.1957G>T had severe language delay, motor developmental regression, autistic behavior and self-aggressive. Patient with c.1973T>C had moderate language delay, poor academic performance, normal motor development but clumsy actions.
Due to the similar locations of the two mutations and the similar phonotypes of the two patients, we considered that iGluR3 and its S2 domain might be a new candidate that play important roles in epilepsy and IDDs. Further functional evidences are needed.
Targeted next-generation sequencing was performed in Chinese children with epilepsy of unknown etiology and intellectual/developmental disabilities (IDDs). Two novel de novo hemizygous missense mutations in GRIA3 (NM_000828: c.1957G>T, p. Ala653Ser and NM_000828: c.1973T>C, p. Val658Ala) was identified, confirmed by Sanger sequencing and predicted as disease causing by Polyphen-2, SIFT, Mutation taster and Align-GVGD. Two mutations are both located at the ligand-binding domain S2, nearing the binding site of glutamate. The two patients were both male. They presented with focal seizures with generalization during sleep before 2yrs old and status epilepticus in the next few years. Brain MRI, metabolic workup and physical examinations were unremarkable. Patient with c.1957G>T had severe language delay, motor developmental regression, autistic behavior and self-aggressive. Patient with c.1973T>C had moderate language delay, poor academic performance, normal motor development but clumsy actions.
Due to the similar locations of the two mutations and the similar phonotypes of the two patients, we considered that iGluR3 and its S2 domain might be a new candidate that play important roles in epilepsy and IDDs. Further functional evidences are needed.