TY - JOUR
T1 - Loss-of-Function Mutations in FRRS1L Lead to an Epileptic-Dyskinetic Encephalopathy
AU - Madeo, Marianna
AU - Stewart, Michelle
AU - Sun, Yuyang
AU - Sahir, Nadia
AU - Wiethoff, Sarah
AU - Chandrasekar, Indra
AU - Yarrow, Anna
AU - Rosenfeld, Jill A.
AU - Yang, Yaping
AU - Cordeiro, Dawn
AU - McCormick, Elizabeth M.
AU - Muraresku, Colleen C.
AU - Jepperson, Tyler N.
AU - McBeth, Lauren J.
AU - Seidahmed, Mohammed Zain
AU - El Khashab, Heba Y.
AU - Hamad, Muddathir
AU - Azzedine, Hamid
AU - Clark, Karl
AU - Corrochano, Silvia
AU - Wells, Sara
AU - Elting, Mariet W.
AU - Weiss, Marjan M.
AU - Burn, Sabrina
AU - Myers, Angela
AU - Landsverk, Megan
AU - Crotwell, Patricia L.
AU - Waisfisz, Quinten
AU - Wolf, Nicole I.
AU - Nolan, Patrick M.
AU - Padilla-Lopez, Sergio
AU - Houlden, Henry
AU - Lifton, Richard
AU - Mane, Shrikant
AU - Singh, Brij B.
AU - Falk, Marni J.
AU - Mercimek-Mahmutoglu, Saadet
AU - Bilguvar, Kaya
AU - Salih, Mustafa A.
AU - Acevedo-Arozena, Abraham
AU - Kruer, Michael C.
N1 - Funding Information:
We thank the families for their gracious participation in these studies. M.C.K. has served as a grant reviewer for the Department of Defense and an advisory committee member for Lundbeck Inc. and receives grant support from Retrophin Inc. Medical Research Council Harwell is a member of the International Mouse Phenotyping Consortium and has received funding from the NIH for generating ( U42OD011174 ) and/or phenotyping ( U54HG006348 ) the Frrs1l-tm1b(EUCOMM)Hmgu mice. The research reported in this publication is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. These studies were also supported by the Deanship of Scientific Research at King Saud University ( RGP-VPP-301 to M.A.S.), by a Sanford Seed Grant (to A.M., P.L.C., and M.C.K.), by the NIH Centers for Mendelian Genomics ( 5U54HG006504 to R.L., K.B., and S.M.), by the NIH National Institute of Neurological Disorders and Stroke ( NS083739 to M.C.K.), by the National Institute of Dental and Craniofacial Research ( DE017102 to B.B.S.), and by a Doris Duke Charitable Foundation Clinical Scientist Development Award ( CSDA2014112 to M.C.K.).
Publisher Copyright:
© 2016 American Society of Human Genetics.
PY - 2016/6/2
Y1 - 2016/6/2
N2 - 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.
AB - 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.
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U2 - 10.1016/j.ajhg.2016.04.008
DO - 10.1016/j.ajhg.2016.04.008
M3 - Article
C2 - 27236917
AN - SCOPUS:84969922984
SN - 0002-9297
VL - 98
SP - 1249
EP - 1255
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 6
ER -