Dataset Information

Loss-of-Function Mutations in FRRS1L Lead to an Epileptic-Dyskinetic Encephalopathy.

ABSTRACT: Glutamatergic neurotransmission governs excitatory signaling in the mammalian brain, and abnormalities of glutamate signaling have been shown to contribute to both epilepsy and hyperkinetic movement disorders. The etiology of many severe childhood movement disorders and epilepsies remains uncharacterized. We describe a neurological disorder with epilepsy and prominent choreoathetosis caused by biallelic pathogenic variants in FRRS1L, which encodes an AMPA receptor outer-core protein. Loss of FRRS1L function attenuates AMPA-mediated currents, implicating chronic abnormalities of glutamatergic neurotransmission in this monogenic neurological disease of childhood.

SUBMITTER: Madeo M

PROVIDER: S-EPMC4908178 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Publications

Loss-of-Function Mutations in FRRS1L Lead to an Epileptic-Dyskinetic Encephalopathy.

Madeo Marianna M Stewart Michelle M Sun Yuyang Y Sahir Nadia N Wiethoff Sarah S Chandrasekar Indra I Yarrow Anna A Rosenfeld Jill A JA Yang Yaping Y Cordeiro Dawn D McCormick Elizabeth M EM Muraresku Colleen C CC Jepperson Tyler N TN McBeth Lauren J LJ Seidahmed Mohammed Zain MZ El Khashab Heba Y HY Hamad Muddathir M Azzedine Hamid H Clark Karl K Corrochano Silvia S Wells Sara S Elting Mariet W MW Weiss Marjan M MM Burn Sabrina S Myers Angela A Landsverk Megan M Crotwell Patricia L PL Waisfisz Quinten Q Wolf Nicole I NI Nolan Patrick M PM Padilla-Lopez Sergio S Houlden Henry H Lifton Richard R Mane Shrikant S Singh Brij B BB Falk Marni J MJ Mercimek-Mahmutoglu Saadet S Bilguvar Kaya K Salih Mustafa A MA Acevedo-Arozena Abraham A Kruer Michael C MC

American journal of human genetics 20160526 6

Glutamatergic neurotransmission governs excitatory signaling in the mammalian brain, and abnormalities of glutamate signaling have been shown to contribute to both epilepsy and hyperkinetic movement disorders. The etiology of many severe childhood movement disorders and epilepsies remains uncharacterized. We describe a neurological disorder with epilepsy and prominent choreoathetosis caused by biallelic pathogenic variants in FRRS1L, which encodes an AMPA receptor outer-core protein. Loss of FRR ...[more]

PMID: 27236917

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Project description:The gene kcnma1 encodes the α-subunit of high-conductance calcium- and voltage-dependent K+ (BK) potassium channel. With the development of generation gene sequencing technology, many KCNMA1 mutants have been identified and are more closely related to generalized epilepsy and paroxysmal dyskinesia. Here, we performed a genetic screen of 26 patients with febrile seizures and identified a novel mutation of KCNMA1 (E155Q). Electrophysiological characterization of different KCNMA1 mutants in HEK 293T cells, the previously-reported R458T and E884K variants (not yet determined), as well as the newly-found E155Q variant, revealed that the current density amplitude of all the above variants was significantly smaller than that of the wild-type (WT) channel. All the above variants caused a positive shift of the I-V curve and played a role through the loss-of-function (LOF) mechanism. Moreover, the β4 subunit slowed down the activation of the E155Q mutant. Then, we used kcnma1 knockout (BK KO) mice as the overall animal model of LOF mutants. It was found that BK KO mice had spontaneous epilepsy, motor impairment, autophagic dysfunction, abnormal electroencephalogram (EEG) signals, as well as possible anxiety and cognitive impairment. In addition, we performed transcriptomic analysis on the hippocampus and cortex of BK KO and WT mice. We identified many differentially expressed genes (DEGs). Eight dysregulated genes [i.e., (Gfap and Grm3 associated with astrocyte activation) (Alpl and Nlrp10 associated with neuroinflammation) (Efna5 and Reln associated with epilepsy) (Cdkn1a and Nr4a1 associated with autophagy)] were validated by RT-PCR, which showed a high concordance with transcriptomic analysis. Calcium imaging results suggested that BK might regulate the autophagy pathway from TRPML1. In conclusion, our study indicated that newly-found point E155Q resulted in a novel loss-of-function variant and the dysregulation of gene expression, especially astrocyte activation, neuroinflammation and autophagy, might be the molecular mechanism of BK-LOF meditated epilepsy.

Dataset Information

Loss-of-Function Mutations in FRRS1L Lead to an Epileptic-Dyskinetic Encephalopathy.

Publications

Loss-of-Function Mutations in FRRS1L Lead to an Epileptic-Dyskinetic Encephalopathy.

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