164016 20240722102836.0 pmc:PMC9232883 pmc 10.1002/mds.28959 doi pmid:35150594 pmid 0885-3185 ISSN 1531-8257 ISSN altmetric:122968845 altmetric DZNE-2022-00679 English 610 Van de Vondel, Liedewei 0000-0003-2214-5908 0 De Novo and Dominantly Inherited SPTAN1 Mutations Cause Spastic Paraplegia and Cerebellar Ataxia. New York, NY 2022 Wiley article DRIVER Output Types/Journal article DataCite Journal Article journal journal PUB:(DE-HGF)16 1721636898_12033 PUB:(DE-HGF) ARTICLE BibTeX JOURNAL_ARTICLE ORCID Journal Article 0 EndNote Pathogenic variants in SPTAN1 have been linked to a remarkably broad phenotypical spectrum. Clinical presentations include epileptic syndromes, intellectual disability, and hereditary motor neuropathy.We investigated the role of SPTAN1 variants in rare neurological disorders such as ataxia and spastic paraplegia.We screened 10,000 NGS datasets across two international consortia and one local database, indicative of the level of international collaboration currently required to identify genes causative for rare disease. We performed in silico modeling of the identified SPTAN1 variants.We describe 22 patients from 14 families with five novel SPTAN1 variants. Of six patients with cerebellar ataxia, four carry a de novo SPTAN1 variant and two show a sporadic inheritance. In this group, one variant (p.Lys2083del) is recurrent in four patients. Two patients have novel de novo missense mutations (p.Arg1098Cys, p.Arg1624Cys) associated with cerebellar ataxia, in one patient accompanied by intellectual disability and epilepsy. We furthermore report a recurrent missense mutation (p.Arg19Trp) in 15 patients with spastic paraplegia from seven families with a dominant inheritance pattern in four and a de novo origin in one case. One further patient carrying a de novo missense mutation (p.Gln2205Pro) has a complex spastic ataxic phenotype. Through protein modeling we show that mutated amino acids are located at crucial interlinking positions, interconnecting the three-helix bundle of a spectrin repeat.We show that SPTAN1 is a relevant candidate gene for ataxia and spastic paraplegia. We suggest that for the mutations identified in this study, disruption of the interlinking of spectrin helices could be a key feature of the pathomechanism. © 2022 International Parkinson and Movement Disorder Society. 353 - Clinical and Health Care Research (POF4-353) G:(DE-HGF)POF4-353 POF4-353 POF IV 0 Dataset connected to CrossRef, PubMed, , Journals: pub.dzne.de ataxia Other next-generation sequencing Other rare diseases Other spastic paraplegia Other spectrin Other Carrier Proteins: genetics MeSH Cerebellar Ataxia: genetics MeSH Humans MeSH Intellectual Disability: genetics MeSH Microfilament Proteins: genetics MeSH Mutation: genetics MeSH Paraplegia: genetics MeSH Pedigree MeSH Phenotype MeSH Spastic Paraplegia, Hereditary: genetics MeSH Spectrin: genetics MeSH De Winter, Jonathan 1 Beijer, Danique 2 Coarelli, Giulia 3 Wayand, Melanie P:(DE-2719)9001023 4 dzne Palvadeau, Robin 0000-0002-4730-6598 5 Pauly, Martje G 0000-0002-7794-0282 6 Klein, Katrin 7 Rautenberg, Maren 8 Guillot-Noël, Léna 9 Deconinck, Tine 10 Vural, Atay 11 Ertan, Sibel 12 Dogu, Okan 13 Uysal, Hilmi 0000-0002-6063-377X 14 Brankovic, Vesna 15 Herzog, Rebecca 0000-0002-5906-5947 16 Brice, Alexis 17 Dürr, Alexandra P:(DE-2719)9000429 18 dzne Klebe, Stephan 19 Stock, Friedrich 20 Bischoff, Almut Turid 21 Rattay, Tim W P:(DE-2719)2811827 22 dzne Sobrido, María-Jesús 0000-0002-6411-1020 23 De Michele, Giovanna 24 De Jonghe, Peter 25 Klopstock, Thomas P:(DE-2719)2810704 26 dzne Lohmann, Katja P:(DE-2719)9000191 27 dzne Zanni, Ginevra 28 Santorelli, Filippo M 29 Timmerman, Vincent 30 Haack, Tobias B 31 Züchner, Stephan 32 Consortium, PREPARE 33 Collaboration Author Schüle, Rebecca P:(DE-2719)2812018 34 dzne Stevanin, Giovanni 35 Synofzik, Matthis P:(DE-2719)2811275 36 dzne Basak, A Nazli 0000-0001-6977-2517 37 Baets, Jonathan 38 10.1002/mds.28959 p. mds.28959 PERI:(DE-600)2041249-6 6 1175-1186 Movement disorders 37 2022 0885-3185 http://pub.dzne.de/record/164016/files/DZNE-2022-00679_Restricted.pdf http://pub.dzne.de/record/164016/files/DZNE-2022-00679_Restricted.pdf?subformat=pdfa pdfa VDB oai:pub.dzne.de:164016 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 4 P:(DE-2719)9001023 External Institute I:(DE-HGF)0 Extern 18 P:(DE-2719)9000429 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 22 P:(DE-2719)2811827 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 26 P:(DE-2719)2810704 External Institute I:(DE-HGF)0 Extern 27 P:(DE-2719)9000191 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 34 P:(DE-2719)2812018 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 36 P:(DE-2719)2811275 DE-HGF Gesundheit Neurodegenerative Diseases G:(DE-HGF)POF4-350 G:(DE-HGF)POF4-353 G:(DE-HGF)POF4 G:(DE-HGF)POF4-300 G:(DE-HGF)POF Clinical and Health Care Research 0 2022 DEAL Wiley StatID:(DE-HGF)3001 StatID 2021-01-30 ger DBCoverage StatID:(DE-HGF)0160 StatID Essential Science Indicators 2021-01-30 WoS StatID:(DE-HGF)0113 StatID Science Citation Index Expanded 2021-01-30 Nationallizenz StatID:(DE-HGF)0420 StatID 2022-11-11 ger JCR StatID:(DE-HGF)0100 StatID MOVEMENT DISORD : 2021 2022-11-11 DBCoverage StatID:(DE-HGF)0200 StatID SCOPUS 2022-11-11 DBCoverage StatID:(DE-HGF)0300 StatID Medline 2022-11-11 DBCoverage StatID:(DE-HGF)0600 StatID Ebsco Academic Search 2022-11-11 Peer Review StatID:(DE-HGF)0030 StatID ASC 2022-11-11 DBCoverage StatID:(DE-HGF)0199 StatID Clarivate Analytics Master Journal List 2022-11-11 DBCoverage StatID:(DE-HGF)0150 StatID Web of Science Core Collection 2022-11-11 DBCoverage StatID:(DE-HGF)1110 StatID Current Contents - Clinical Medicine 2022-11-11 DBCoverage StatID:(DE-HGF)1030 StatID Current Contents - Life Sciences 2022-11-11 IF >= 5 StatID:(DE-HGF)9905 StatID MOVEMENT DISORD : 2021 2022-11-11 I:(DE-2719)1210000 AG Gasser Parkinson Genetics 0 I:(DE-2719)1240005 Core ICRU Core ICRU 1 I:(DE-2719)1111015 Clinical Research (Munich) Clinical Research (Munich) 2 journal VDB I:(DE-2719)1210000 I:(DE-2719)1240005 I:(DE-2719)1111015 UNRESTRICTED