title: 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.
authors.affiliation: Children's Health Research Center, Sanford Research, Sioux Falls, SD 57104, USA.
authors.forename: Marianna
authors.initials: M
authors.lastname: Madeo
authors.affiliation: Mammalian Genetics Unit, Medical Research Council Harwell, Oxfordshire OX11 ORD, UK.
authors.forename: Michelle
authors.initials: M
authors.lastname: Stewart
authors.affiliation: Department of Basic Sciences, University of North Dakota, Grand Forks, ND 58202, USA.
authors.forename: Yuyang
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Children's Health Research Center, Sanford Research, Sioux Falls, SD 57104, USA.
authors.forename: Nadia
authors.initials: N
authors.lastname: Sahir
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Wiethoff
authors.affiliation: Children's Health Research Center, Sanford Research, Sioux Falls, SD 57104, USA.
authors.forename: Indra
authors.initials: I
authors.lastname: Chandrasekar
authors.affiliation: Children's Health Research Center, Sanford Research, Sioux Falls, SD 57104, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Yarrow
authors.affiliation: Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Jill A
authors.initials: JA
authors.lastname: Rosenfeld
authors.affiliation: Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Division of Clinical & Metabolic Genetics and Genetics & Genome Biology Program, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON M5G 1X8, Canada.
authors.forename: Dawn
authors.initials: D
authors.lastname: Cordeiro
authors.affiliation: Division of Human Genetics, The Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: McCormick
authors.affiliation: Division of Human Genetics, The Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Colleen C
authors.initials: CC
authors.lastname: Muraresku
authors.affiliation: Children's Health Research Center, Sanford Research, Sioux Falls, SD 57104, USA.
authors.forename: Tyler N
authors.initials: TN
authors.lastname: Jepperson
authors.affiliation: Children's Health Research Center, Sanford Research, Sioux Falls, SD 57104, USA.
authors.forename: Lauren J
authors.initials: LJ
authors.lastname: McBeth
authors.affiliation: Department of Pediatrics, Security Forces Hospital, Riyadh 12625, Saudi Arabia.
authors.forename: Mohammed Zain
authors.initials: MZ
authors.lastname: Seidahmed
authors.affiliation: Division of Pediatric Neurology, Department of Pediatrics, College of Medicine, King Saud University, Riyadh 12372, Saudi Arabia; Department of Pediatrics, The Children's Hospital, Ain Shams University, Cairo 11355, Egypt.
authors.forename: Heba Y
authors.initials: HY
authors.lastname: El Khashab
authors.affiliation: Division of Pediatric Neurology, Department of Pediatrics, College of Medicine, King Saud University, Riyadh 12372, Saudi Arabia.
authors.forename: Muddathir
authors.initials: M
authors.lastname: Hamad
authors.affiliation: Institute of Neuropathology, Uniklinik RWTH Aachen, Aachen 52074, Germany.
authors.forename: Hamid
authors.initials: H
authors.lastname: Azzedine
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Karl
authors.initials: K
authors.lastname: Clark
authors.affiliation: Mammalian Genetics Unit, Medical Research Council Harwell, Oxfordshire OX11 ORD, UK.
authors.forename: Silvia
authors.initials: S
authors.lastname: Corrochano
authors.affiliation: Mammalian Genetics Unit, Medical Research Council Harwell, Oxfordshire OX11 ORD, UK.
authors.forename: Sara
authors.initials: S
authors.lastname: Wells
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam 1007, the Netherlands.
authors.forename: Mariet W
authors.initials: MW
authors.lastname: Elting
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam 1007, the Netherlands.
authors.forename: Marjan M
authors.initials: MM
authors.lastname: Weiss
authors.affiliation: Children's Health Research Center, Sanford Research, Sioux Falls, SD 57104, USA.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Burn
authors.affiliation: Children's Health Research Center, Sanford Research, Sioux Falls, SD 57104, USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Myers
authors.affiliation: Children's Health Research Center, Sanford Research, Sioux Falls, SD 57104, USA.
authors.forename: Megan
authors.initials: M
authors.lastname: Landsverk
authors.affiliation: Children's Health Research Center, Sanford Research, Sioux Falls, SD 57104, USA.
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Crotwell
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam 1007, the Netherlands.
authors.forename: Quinten
authors.initials: Q
authors.lastname: Waisfisz
authors.affiliation: Department of Child Neurology and Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam 1007, the Netherlands.
authors.forename: Nicole I
authors.initials: NI
authors.lastname: Wolf
authors.affiliation: Mammalian Genetics Unit, Medical Research Council Harwell, Oxfordshire OX11 ORD, UK.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Nolan
authors.affiliation: Department of Child Health, University of Arizona College of Medicine, Phoenix, AZ 85004, USA; Neurogenetics Research Program, Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ 85016, USA.
authors.forename: Sergio
authors.initials: S
authors.lastname: Padilla-Lopez
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Henry
authors.initials: H
authors.lastname: Houlden
authors.affiliation: Department of Genetics and Yale Center for Genome Analysis, Yale School of Medicine, New Haven, CT 06516, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Lifton
authors.affiliation: Department of Genetics and Yale Center for Genome Analysis, Yale School of Medicine, New Haven, CT 06516, USA.
authors.forename: Shrikant
authors.initials: S
authors.lastname: Mane
authors.affiliation: Department of Basic Sciences, University of North Dakota, Grand Forks, ND 58202, USA.
authors.forename: Brij B
authors.initials: BB
authors.lastname: Singh
authors.affiliation: Division of Human Genetics, The Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Marni J
authors.initials: MJ
authors.lastname: Falk
authors.affiliation: Division of Clinical & Metabolic Genetics and Genetics & Genome Biology Program, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON M5G 1X8, Canada.
authors.forename: Saadet
authors.initials: S
authors.lastname: Mercimek-Mahmutoglu
authors.affiliation: Department of Genetics and Yale Center for Genome Analysis, Yale School of Medicine, New Haven, CT 06516, USA.
authors.forename: Kaya
authors.initials: K
authors.lastname: Bilguvar
authors.affiliation: Division of Pediatric Neurology, Department of Pediatrics, College of Medicine, King Saud University, Riyadh 12372, Saudi Arabia.
authors.forename: Mustafa A
authors.initials: MA
authors.lastname: Salih
authors.affiliation: Mammalian Genetics Unit, Medical Research Council Harwell, Oxfordshire OX11 ORD, UK.
authors.forename: Abraham
authors.initials: A
authors.lastname: Acevedo-Arozena
authors.affiliation: Children's Health Research Center, Sanford Research, Sioux Falls, SD 57104, USA; Department of Child Health, University of Arizona College of Medicine, Phoenix, AZ 85004, USA; Neurogenetics Research Program, Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ 85016, USA; Program in Neuroscience, Arizona State University, Tempe, AZ 85287, USA; Pediatric Movement Disorders Center, Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ 85016, USA. Electronic address: mkruer@phoenixchildrens.com.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Kruer
mesh_terms: D001927:Brain Diseases / Q000235:genetics*; D004594:Electrophysiology; D004827:Epilepsy / Q000235:genetics*; D005260:Female; D006801:Humans; D006948:Hyperkinesis / Q000235:genetics*; D007223:Infant; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010375:Pedigree; D009435:Synaptic Transmission / Q000502:physiology*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000378:metabolism
chemical_list: C403268:FRRS1L protein, human; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid