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

Marianna Madeo, Michelle Stewart, Yuyang Sun, Nadia Sahir, Sarah Wiethoff, Indra Chandrasekar, Anna Yarrow, Jill A. Rosenfeld, Yaping Yang, Dawn Cordeiro, Elizabeth M. McCormick, Colleen C. Muraresku, Tyler N. Jepperson, Lauren J. McBeth, Mohammed Zain Seidahmed, Heba Y. El Khashab, Muddathir Hamad, Hamid Azzedine, Karl Clark, Silvia CorrochanoSara Wells, Mariet W. Elting, Marjan M. Weiss, Sabrina Burn, Angela Myers, Megan Landsverk, Patricia L. Crotwell, Quinten Waisfisz, Nicole I. Wolf, Patrick M. Nolan, Sergio Padilla-Lopez, Henry Houlden, Richard Lifton, Shrikant Mane, Brij B. Singh, Marni J. Falk, Saadet Mercimek-Mahmutoglu, Kaya Bilguvar, Mustafa A. Salih, Abraham Acevedo-Arozena, Michael C. Kruer

Research output: Contribution to journalArticle

21 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1249-1255
Number of pages7
JournalAmerican Journal of Human Genetics
Volume98
Issue number6
DOIs
StatePublished - Jun 2 2016
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Madeo, M., Stewart, M., Sun, Y., Sahir, N., Wiethoff, S., Chandrasekar, I., Yarrow, A., Rosenfeld, J. A., Yang, Y., Cordeiro, D., McCormick, E. M., Muraresku, C. C., Jepperson, T. N., McBeth, L. J., Seidahmed, M. Z., El Khashab, H. Y., Hamad, M., Azzedine, H., Clark, K., ... Kruer, M. C. (2016). Loss-of-Function Mutations in FRRS1L Lead to an Epileptic-Dyskinetic Encephalopathy. American Journal of Human Genetics, 98(6), 1249-1255. https://doi.org/10.1016/j.ajhg.2016.04.008