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De Novo and Dominantly Inherited SPTAN1 Mutations Cause Spastic Paraplegia and Cerebellar Ataxia.
Van de Vondel, Liedewei; De Winter, Jonathan; Beijer, Danique; Coarelli, Giulia; Wayand, Melanie; Palvadeau, Robin; Pauly, Martje G; Klein, Katrin; Rautenberg, Maren; Guillot-Noël, Léna; Deconinck, Tine; Vural, Atay; Ertan, Sibel; Dogu, Okan; Uysal, Hilmi; Brankovic, Vesna; Herzog, Rebecca; Brice, Alexis; Durr, Alexandra; Klebe, Stephan; Stock, Friedrich; Bischoff, Almut Turid; Rattay, Tim W; Sobrido, María-Jesús; De Michele, Giovanna; De Jonghe, Peter; Klopstock, Thomas; Lohmann, Katja; Zanni, Ginevra; Santorelli, Filippo M; Timmerman, Vincent; Haack, Tobias B; Züchner, Stephan; Schüle, Rebecca; Stevanin, Giovanni; Synofzik, Matthis; Basak, A Nazli; Baets, Jonathan.
Afiliação
  • Van de Vondel L; Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.
  • De Winter J; Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
  • Beijer D; Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.
  • Coarelli G; Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
  • Wayand M; Neuromuscular Reference Centre, Department of Neurology, Antwerp University Hospital, Antwerp, Belgium.
  • Palvadeau R; Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.
  • Pauly MG; Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
  • Klein K; Dr John T. Macdonald Foundation Department of Human Genetics, John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.
  • Rautenberg M; Sorbonne University, ICM-Paris Brain Institute, INSERM, CNRS, APHP, Pitié Salpêtrière Hospital, Paris, France.
  • Guillot-Noël L; Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research (HIH), Center of Neurology, University of Tübingen, Tübingen, Germany.
  • Deconinck T; German Center for Neurodegenerative Diseases (DZNE), University of Tübingen, Tübingen, Germany.
  • Vural A; Koc University, School of Medicine, Suna and Inan Kirac Foundation, Istanbul, Turkey.
  • Ertan S; Department of Neurology, University Hospital Schleswig Holstein, Lübeck, Germany.
  • Dogu O; Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.
  • Uysal H; Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tübingen, Germany.
  • Brankovic V; Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tübingen, Germany.
  • Herzog R; Sorbonne University, ICM-Paris Brain Institute, INSERM, CNRS, APHP, Pitié Salpêtrière Hospital, Paris, France.
  • Brice A; Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Edegem, Belgium.
  • Durr A; School of Medicine, Department of Neurology, Koc University, Istanbul, Turkey.
  • Klebe S; School of Medicine, Department of Neurology, Koc University, Istanbul, Turkey.
  • Stock F; Department of Neurology, School of Medicine, Mersin University, Mersin, Turkey.
  • Bischoff AT; Department of Neurology, School of Medicine, Akdeniz University, Antalya, Turkey.
  • Rattay TW; Clinic for Child Neurology and Psychiatry, University of Belgrade, Belgrade, Serbia.
  • Sobrido MJ; Department of Neurology, University Hospital Schleswig Holstein, Lübeck, Germany.
  • De Michele G; Sorbonne University, ICM-Paris Brain Institute, INSERM, CNRS, APHP, Pitié Salpêtrière Hospital, Paris, France.
  • De Jonghe P; Sorbonne University, ICM-Paris Brain Institute, INSERM, CNRS, APHP, Pitié Salpêtrière Hospital, Paris, France.
  • Klopstock T; Department of Neurology, University Hospital Essen, Essen, Germany.
  • Lohmann K; Institute of Human Genetics, University Hospital Essen, Essen, Germany.
  • Zanni G; Department of Neurology, Friedrich-Baur-Institute, LMU Munich, Munich, Germany.
  • Santorelli FM; Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research (HIH), Center of Neurology, University of Tübingen, Tübingen, Germany.
  • Timmerman V; German Center for Neurodegenerative Diseases (DZNE), University of Tübingen, Tübingen, Germany.
  • Haack TB; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Santiago de Compostela, Spain.
  • Züchner S; Neurogenetics Research Group, Instituto de Investigación Sanitaria (IDIS), Hospital Clínico Universitario, SERGAS, Santiago de Compostela, Spain.
  • Schüle R; Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
  • Stevanin G; Neuromuscular Reference Centre, Department of Neurology, Antwerp University Hospital, Antwerp, Belgium.
  • Synofzik M; Department of Neurology, Friedrich-Baur-Institute, LMU Munich, Munich, Germany.
  • Basak AN; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
  • Baets J; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
Mov Disord ; 37(6): 1175-1186, 2022 06.
Article em En | MEDLINE | ID: mdl-35150594
BACKGROUND: Pathogenic variants in SPTAN1 have been linked to a remarkably broad phenotypical spectrum. Clinical presentations include epileptic syndromes, intellectual disability, and hereditary motor neuropathy. OBJECTIVES: We investigated the role of SPTAN1 variants in rare neurological disorders such as ataxia and spastic paraplegia. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Paraplegia Espástica Hereditária / Proteínas de Transporte / Ataxia Cerebelar / Deficiência Intelectual / Proteínas dos Microfilamentos Limite: Humans Idioma: En Revista: Mov Disord Assunto da revista: NEUROLOGIA Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Bélgica

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Paraplegia Espástica Hereditária / Proteínas de Transporte / Ataxia Cerebelar / Deficiência Intelectual / Proteínas dos Microfilamentos Limite: Humans Idioma: En Revista: Mov Disord Assunto da revista: NEUROLOGIA Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Bélgica