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Brief Communication Mutations in AMPA Receptor-Associated FRRS1L

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Brief Communication Mutations in AMPA Receptor-Associated FRRS1L Brief Communication Mutations in AMPA receptor-associated FRRS1L lead to a hyperkinetic movement disorder in mice and humans Marianna Madeo1*, Michelle Stewart2*, Yuyang Sun3, Nadia Sahir1, Sarah Wiethoff4, Indra Chandrasekar1, Anna Yarrow1, Jill A Mokry5, Yaping Yang5, Dawn Cordeiro6, Elizabeth M McCormick7, Colleen C Murarescu7, Tyler N. Jepperson1, Lauren McBeth1, Mohammed Zain Seidahmed8, Heba El Khashab9,10, Muddathir Hamad9, Hamid Azzedine11, Karl Clark12, Silvia Corrochano2, Sara Wells2, Mariet W Elting13, Marjan M Weiss13, Sabrina Burn1, Angela Myers1, Megan Landsverk1, Patricia L Crotwell1, Quinten Waisfisz13, Nicole I. Wolf14, Patrick M. Nolan2, Sergio Padilla-Lopez15,16, Henry Houlden4, Richard Lifton17, Shrikant Mane17, Brij Singh3, Marni Falk7*, Saadet Mercimek-Mahmutoglu6*, Mustafa A. Salih9*, Kaya Bilguvar17*, Abraham Acevedo- Arozena2*, Michael C. Kruer1,15,16,18,19*# 1 Children’s Health Research Center, Sanford Research Sioux Falls, SD 57104 USA 2 MRC Harwell, Mammalian Genetics Unit Oxfordshire, OX11 ORD, UK 3 Department of Basic Sciences University of North Dakota Grand Forks, ND 58202 USA 4 Department of Molecular Neuroscience, Lila Reta Weston Institute of Neurology, University College London London WC1H 0AJ UK 5 Department of Molecular & Human Genetics, Baylor College of Medicine Houston, TX, 77030 USA 6 Department of Pediatrics, Division of Clinical & Metabolic Genetics and Genetics & Genome Biology Program, The Hospital for Sick Children, University of Toronto Toronto, Ontario, M5G 1X8 Canada 7 Department of Pediatrics, Division of Human Genetics and Division of Child Development & Metabolic Disease, The Children's Hospital of Philadelphia Philadelphia, PA, 19104 USA 8 Department of Pediatrics, Security Forces Hospital Riyadh, 12625 Saudi Arabia 9 Department of Pediatrics, Division of Pediatric Neurology, College of Medicine, King Saud University Riyadh, 12372 Saudi Arabia 10 Department of Pediatrics, Ain Shams University Hospital Cairo, 11355 Egypt 11 Institute of Neuropathology, Uniklink-RWTH 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 16 Neurogenetics Research Program, Barrow Neurological Institute, Phoenix Children’s Hospital, Phoenix, AZ, 85016 USA 17 Yale Genomics Center New Haven, CT, 06516 USA 18 Program in Neuroscience, Arizona State University Tempe, AZ, 85287 USA 19 Movement Disorders Center, Barrow Neurological Institute, Phoenix Children’s Hospital, Phoenix, AZ, 85016 USA * These authors contributed equally Author emails: Marianna Madeo [email protected] Michelle Stewart [email protected] Yuyang Sun [email protected] Nadia Sahir [email protected] Sarah Wiethoff [email protected] Indra Chandrasekar [email protected] Anna Yarrow [email protected] Jill Mokry [email protected] Yaping Yang [email protected] Dawn Cordeiro [email protected] Elizabeth McCormick [email protected] Colleen Murarescu [email protected] Tyler Jepperson [email protected] Lauren McBeth [email protected] Mohammed Seidahmed [email protected] Heba El Khashab [email protected] Muddathir Hamad [email protected] Hamid Azzedine [email protected] Karl Clark [email protected] Silvia Corrochano [email protected] Sara Wells [email protected] Mariet Elting [email protected] Marjan Weiss [email protected] Sabrina Burn [email protected] Angela Myers [email protected] Megan Landsverk [email protected] Patricia Crotwell [email protected] Quinten Waisfisz [email protected] Nicole Wolf [email protected] Pat Nolan [email protected] Sergio Padilla-Lopez [email protected] Henry Houlden [email protected] Rick Lifton [email protected] Shrikant Mane [email protected] Brij Singh [email protected] Marni Falk [email protected] Saadet Mercimek-Mahmutoglu [email protected] Mustafa Salih [email protected] Kaya Bilguvar [email protected] Abraham Acevedo-Arozena [email protected] Michael Kruer [email protected] Correspondence should be addressed to M.C.K. ([email protected]) The etiology of many severe childhood movement disorders remains uncharacterized. We describe a novel neurological disorder with prominent hyperkinetic movements in both mice and humans caused by mutations in FRRS1L, 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. Pediatric movement disorders encompass a heterogeneous group of neurodevelopmental and neurodegenerative disorders affecting movement and limiting activities of daily living (1). Huntington disease (HD) is a progressive neurodegenerative disease characterized by impairment of volitional movement, chorea and subcortical dementia due to a CAG triplet repeat expansion in HTT. Although uncommon, juvenile HD (JHD) represents an important cause of pediatric movement disorders (2). Although the majority of patients with clinical features of HD will ultimately be found to have an expanded HTT allele, several phenocopies have been described, yet the cause of most HD-like syndromes remains uncharacterized (3). We set out to identify genes that lead to HD-like phenotypes and enrolled eligible families in our institutional review board and ethics committee-approved studies after informed consent was obtained. The index family hailed from southern Saudi Arabia, and the parents were distant cousins (Supplementary Figure 1a). All five of the couple’s children developed progressive chorea, dementia and epilepsy without expansion of HTT (Supplementary Table 1). Over time, a rigid, akinetic presentation began to predominate. One child had already succumbed to the disease at the time of ascertainment. All laboratory studies were unrevealing. Brain MRI was initially normal, but repeat neuroimaging demonstrated diffuse cortical and cerebellar volume loss with flattening of the caudate heads (Supplementary Figure 1b). Given the family structure and presumed autosomal recessive nature of the disorder, we then applied tandem homozygosity mapping and whole exome sequencing. We identified six regions of homozygosity >3 Mb shared by affected family members alone (Supplementary Table 2). We performed whole exome sequencing on patients 1_II:-1-4 and focused our analysis on homozygous stop-gain, stop-loss, or frameshift and splice-site or missense variants predicted to be deleterious. We excluded variants with a reported minor allele frequency >0.01 based on ExAc Browser and Exome Variant Server databases. Using this strategy, we identified a homozygous c.961C>T (p.G321*) mutation in FRRS1L (aka c9orf4) (NM_014334) within a prominent block of homozygosity (hg19; chr9:104,622,396-119,149,440). We confirmed segregation within affected family members by Sanger sequencing (Supplementary Figure 1a). This mutation has not been reported in variation repositories, and is predicted to lead to loss of a C-terminal hydrophobic motif that may contribute to FRRS1L’s membrane localization (Figure 1a). We subsequently identified three additional, unrelated patients with similar phenotypes (Supplemental Video 1) by whole exome sequencing [patient 2_II-1: homozygous c.845G>A (p.W282*)]; patient 3_II-1: homozygous c.737_739del (p.G246del)]; patient 4_II-2 c.436dup; (p.Ile146Asnfs*10) (Supplementary Table 1) and confirmed mutations by Sanger sequencing (Supplementary Figure 1a). None of these variants has been identified in public repositories. Targeted sequencing of FRRS1L in a cohort of 52 pediatric and adult patients with an early- onset Huntington-like phenotype but without demonstrable mutations in HTT did not reveal any putatively pathogenic biallelic mutations (Supplementary Table 3). Additionally, no biallelic FRRS1L mutations were detected in the Epi4K and EuroEPINOMICS RES epilepsy consortia datasets. Using patient fibroblasts and age and sex-matched controls, we next performed RT-PCR to determine whether the c.961C>T and c.845G>A mRNAs are subject to nonsense-mediated decay. Although FRRS1L is predominantly expressed in the brain (Supplementary Figure 2a), it is expressed at a lower level in fibroblasts (4) (Figure 1b). For both c.961C>T and c.845G>A, consistent with a mutation location near the 3’ end of the transcript, we found equal levels of both control and mutant transcripts (Supplementary Figure 2b). Both the (p.G321*) and (p.W282*) patient fibroblasts exhibited a marked decrease in FRRS1L levels by immunoblot (Figure 1b). Little is known about the biological function of FRRS1L. Despite its name (ferric chelate reductase-like 1), it lacks a ferrochelatase domain, and so is unlikely to function in iron storage and processing. A recent study instead identified FRRS1L as an important component of the outer core of AMPA glutamate receptor accessory proteins (5), suggesting that loss of FRRS1L would affect AMPA receptor constituency and might affect AMPA receptor function. In that study, FRRS1L co-immunoprecipitated with GluR1, suggesting a direct interaction
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