Loss-of-Function Mutations in FRRS1L Lead to an Epileptic-Dyskinetic Encephalopathy PMID: 27236917

ADC Targets in Oncology

2026-04-10

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

Am J Hum Genet. 2016 Jun 2;98(6):1249-1255. doi: 10.1016/j.ajhg.2016.04.008.

Marianna Madeo ¹ , Michelle Stewart ² , Yuyang Sun ³ , Nadia Sahir ¹ , Sarah Wiethoff ⁴ , Indra Chandrasekar ¹ , Anna Yarrow ¹ , Jill A Rosenfeld ⁵ , Yaping Yang ⁵ , Dawn Cordeiro ⁶ , Elizabeth M McCormick ⁷ , Colleen C Muraresku ⁷ , Tyler N Jepperson ¹ , Lauren J McBeth ¹ , Mohammed Zain Seidahmed ⁸ , Heba Y El Khashab ⁹ , Muddathir Hamad ¹⁰ , Hamid Azzedine ¹¹ , Karl Clark ¹² , Silvia Corrochano ² , Sara Wells ² , Mariet W Elting ¹³ , Marjan M Weiss ¹³ , Sabrina Burn ¹ , Angela Myers ¹ , Megan Landsverk ¹ , Patricia L Crotwell ¹ , Quinten Waisfisz ¹³ , Nicole I Wolf ¹⁴ , Patrick M Nolan ² , Sergio Padilla-Lopez ¹⁵ , Henry Houlden ⁴ , Richard Lifton ¹⁶ , Shrikant Mane ¹⁶ , Brij B Singh ³ , Marni J Falk ⁷ , Saadet Mercimek-Mahmutoglu ⁶ , Kaya Bilguvar ¹⁶ , Mustafa A Salih ¹⁰ , Abraham Acevedo-Arozena ² , Michael C Kruer ¹⁷

Affiliations

1. Children's Health Research Center, Sanford Research, Sioux Falls, SD 57104, USA.
2. Mammalian Genetics Unit, Medical Research Council Harwell, Oxfordshire OX11 ORD, UK.
3. Department of Basic Sciences, University of North Dakota, Grand Forks, ND 58202, USA.
4. Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
5. Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
6. 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.
7. Division of Human Genetics, The Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
8. Department of Pediatrics, Security Forces Hospital, Riyadh 12625, Saudi Arabia.
9. 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.
10. Division of Pediatric Neurology, Department of Pediatrics, College of Medicine, King Saud University, Riyadh 12372, Saudi Arabia.
11. Institute of Neuropathology, Uniklinik RWTH Aachen, Aachen 52074, Germany.
12. Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA.
13. Department of Clinical Genetics, VU University Medical Center, Amsterdam 1007, the Netherlands.
14. Department of Child Neurology and Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam 1007, the Netherlands.
15. 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.
16. Department of Genetics and Yale Center for Genome Analysis, Yale School of Medicine, New Haven, CT 06516, USA.
17. 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: [email protected].

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.