Volume 37, Issue 6 p. 1175-1186
Research Article

De Novo and Dominantly Inherited SPTAN1 Mutations Cause Spastic Paraplegia and Cerebellar Ataxia

Liedewei Van de Vondel MSc

Liedewei Van de Vondel MSc

Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium

Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium

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Jonathan De Winter MD

Jonathan De Winter MD

Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium

Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium

Neuromuscular Reference Centre, Department of Neurology, Antwerp University Hospital, Antwerp, Belgium

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Danique Beijer PhD

Danique Beijer PhD

Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium

Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium

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

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Giulia Coarelli MD

Giulia Coarelli MD

Sorbonne University, ICM-Paris Brain Institute, INSERM, CNRS, APHP, Pitié Salpêtrière Hospital, Paris, France

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Melanie Wayand MD

Melanie Wayand MD

Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research (HIH), Center of Neurology, University of Tübingen, Tübingen, Germany

German Center for Neurodegenerative Diseases (DZNE), University of Tübingen, Tübingen, Germany

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Robin Palvadeau MSc

Robin Palvadeau MSc

Koc University, School of Medicine, Suna and Inan Kirac Foundation, Istanbul, Turkey

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Martje G. Pauly MD

Martje G. Pauly MD

Department of Neurology, University Hospital Schleswig Holstein, Lübeck, Germany

Institute of Neurogenetics, University of Lübeck, Lübeck, Germany

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Katrin Klein PhD

Katrin Klein PhD

Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tübingen, Germany

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Maren Rautenberg PhD

Maren Rautenberg PhD

Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tübingen, Germany

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Léna Guillot-Noël MSc

Léna Guillot-Noël MSc

Sorbonne University, ICM-Paris Brain Institute, INSERM, CNRS, APHP, Pitié Salpêtrière Hospital, Paris, France

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Tine Deconinck MSc

Tine Deconinck MSc

Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Edegem, Belgium

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Atay Vural MD

Atay Vural MD

School of Medicine, Department of Neurology, Koc University, Istanbul, Turkey

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Sibel Ertan MD, PhD

Sibel Ertan MD, PhD

School of Medicine, Department of Neurology, Koc University, Istanbul, Turkey

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Okan Dogu MD, PhD

Okan Dogu MD, PhD

Department of Neurology, School of Medicine, Mersin University, Mersin, Turkey

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Hilmi Uysal MD, PhD

Hilmi Uysal MD, PhD

Department of Neurology, School of Medicine, Akdeniz University, Antalya, Turkey

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Vesna Brankovic MD

Vesna Brankovic MD

Clinic for Child Neurology and Psychiatry, University of Belgrade, Belgrade, Serbia

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Rebecca Herzog MD, PhD

Rebecca Herzog MD, PhD

Department of Neurology, University Hospital Schleswig Holstein, Lübeck, Germany

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Alexis Brice MD

Alexis Brice MD

Sorbonne University, ICM-Paris Brain Institute, INSERM, CNRS, APHP, Pitié Salpêtrière Hospital, Paris, France

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Alexandra Durr MD, PhD

Alexandra Durr MD, PhD

Sorbonne University, ICM-Paris Brain Institute, INSERM, CNRS, APHP, Pitié Salpêtrière Hospital, Paris, France

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Stephan Klebe MD, PhD

Stephan Klebe MD, PhD

Department of Neurology, University Hospital Essen, Essen, Germany

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Friedrich Stock MD

Friedrich Stock MD

Institute of Human Genetics, University Hospital Essen, Essen, Germany

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Almut Turid Bischoff MD

Almut Turid Bischoff MD

Department of Neurology, Friedrich-Baur-Institute, LMU Munich, Munich, Germany

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Tim W. Rattay MD, PhD

Tim W. Rattay MD, PhD

Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research (HIH), Center of Neurology, University of Tübingen, Tübingen, Germany

German Center for Neurodegenerative Diseases (DZNE), University of Tübingen, Tübingen, Germany

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María-Jesús Sobrido MD, PhD

María-Jesús Sobrido MD, PhD

Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Santiago de Compostela, Spain

Neurogenetics Research Group, Instituto de Investigación Sanitaria (IDIS), Hospital Clínico Universitario, SERGAS, Santiago de Compostela, Spain

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Giovanna De Michele MD

Giovanna De Michele MD

Department of Neurosciences and Reproductive and Odontostomatological Sciences, Federico II University, Naples, Italy

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Peter De Jonghe MD, PhD

Peter De Jonghe MD, PhD

Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium

Neuromuscular Reference Centre, Department of Neurology, Antwerp University Hospital, Antwerp, Belgium

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Thomas Klopstock MD, PhD

Thomas Klopstock MD, PhD

Department of Neurology, Friedrich-Baur-Institute, LMU Munich, Munich, Germany

German Center for Neurodegenerative Diseases (DZNE), Munich, Germany

Munich Cluster for Systems Neurology (SyNergy), Munich, Germany

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Katja Lohmann PhD

Katja Lohmann PhD

Institute of Neurogenetics, University of Lübeck, Lübeck, Germany

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Ginevra Zanni MD, PhD

Ginevra Zanni MD, PhD

Unit of Neuromuscular and Neurodegenerative Disorders, Department of Neurosciences, Bambino Gesù Children's Hospital, Rome, Italy

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Filippo M. Santorelli MD, PhD

Filippo M. Santorelli MD, PhD

Molecular Medicine, IRCCS Fondazione Stella Maris, Pisa, Italy

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Vincent Timmerman PhD

Vincent Timmerman PhD

Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium

Peripheral Neuropathy Research Group, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium

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Tobias B. Haack MD

Tobias B. Haack MD

Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tübingen, Germany

Centre for Rare Diseases, University of Tübingen, Tübingen, Germany

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Stephan Züchner MD, PhD

Stephan Züchner MD, PhD

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

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PREPARE ConsortiumRebecca Schüle MD, PhD

Rebecca Schüle MD, PhD

Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research (HIH), Center of Neurology, University of Tübingen, Tübingen, Germany

German Center for Neurodegenerative Diseases (DZNE), University of Tübingen, Tübingen, Germany

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Giovanni Stevanin PhD

Giovanni Stevanin PhD

Sorbonne University, ICM-Paris Brain Institute, INSERM, CNRS, APHP, Pitié Salpêtrière Hospital, Paris, France

Paris Sciences Lettres Research University, Ecole Pratique des Hautes Etudes, Paris, France

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Matthis Synofzik MD, PhD

Matthis Synofzik MD, PhD

Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research (HIH), Center of Neurology, University of Tübingen, Tübingen, Germany

German Center for Neurodegenerative Diseases (DZNE), University of Tübingen, Tübingen, Germany

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A. Nazli Basak PhD

A. Nazli Basak PhD

Koc University, School of Medicine, Suna and Inan Kirac Foundation, Istanbul, Turkey

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Jonathan Baets MD, PhD

Corresponding Author

Jonathan Baets MD, PhD

Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium

Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium

Neuromuscular Reference Centre, Department of Neurology, Antwerp University Hospital, Antwerp, Belgium

Correspondence to: Prof. Jonathan Baets, University of Antwerp – CDE Universiteitsplein 1, B-2610 Wilrijk, Belgium; E-mail: [email protected]

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First published: 12 February 2022
Citations: 6

Financial disclosure: This work was supported by the EU Horizon 2020 program (Solve-RD under grant agreement N°779257), the Association Belge contre les Maladies Neuromusculaires (ABMM), and the University of Antwerp under Grant Agreement KP-BOF-2021, N°FFB210049. J.B. is supported by a Senior Clinical Researcher mandate of the Research Fund - Flanders (FWO) under grant agreement N°1805021N. L.V.deV. is supported by a predoctoral fellowship of the FWO under grant agreement N°11F0921N. J.D.W. is supported by the Goldwasser-Emsens fellowship. K.L. is funded by a research grant from the Damp Foundation. M.G.P. is funded by the Clinician Scientist School Luebeck (DFG-GEPRIS, project N°413535489). T.B.H. was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation, projects N°418081722 and N°433158657. This work was further supported by the Bundesministerium für Forschung und Bildung (BMBF) through funding for the TreatHSP network (N°01GM1905 to R.S. and S.K.), the National Institute of Health (NIH/NINDS) (grant N°5R01NS072248 to R.S. and S.Z.), the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation, N°441409627), as part of the PROSPAX consortium under the frame of EJP RD, the European Joint Programme on Rare Diseases, under the EJP RD COFUND-EJP N°825575 (to M.S., R.S., N.B., F.S., A.D., and to S.K. and S.Z. as associated partners), and the HSP Selbsthilfegruppe e.V. (grant to R.S.). T.W.R. was supported by the Clinician Scientist program (Grant N°386-0-0), University of Tübingen, Medical Faculty.

Conflict of interest: The authors report no conflict of interest.

ABSTRACT

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

Data Availability Statement

The raw NGS data supporting the findings in patients cannot be made publicly available for confidentiality policies in the consortia involved. The NGS data in Solve-RD is available through the RD-Connect GPAP after an embargo period of 6 months. All other data generated or analyses during this study are available upon reasonable request.