Liedewei Van de Vondel1,2, Jonathan De Winter1,2,3, Danique Beijer1,2,4, Giulia Coarelli5, Melanie Wayand6,7, Robin Palvadeau8, Martje G Pauly9,10, Katrin Klein11, Maren Rautenberg11, Léna Guillot-Noël5, Tine Deconinck12, Atay Vural13, Sibel Ertan13, Okan Dogu14, Hilmi Uysal15, Vesna Brankovic16, Rebecca Herzog9, Alexis Brice5, Alexandra Durr5, Stephan Klebe17, Friedrich Stock18, Almut Turid Bischoff19, Tim W Rattay6,7, María-Jesús Sobrido20,21, Giovanna De Michele22, Peter De Jonghe2,3, Thomas Klopstock19,23,24, Katja Lohmann10, Ginevra Zanni25, Filippo M Santorelli26, Vincent Timmerman2,27, Tobias B Haack11,28, Stephan Züchner4, Rebecca Schüle6,7, Giovanni Stevanin5,29, Matthis Synofzik6,7, A Nazli Basak8, Jonathan Baets1,2,3. 1. Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium. 2. Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. 3. Neuromuscular Reference Centre, Department of Neurology, Antwerp University Hospital, Antwerp, Belgium. 4. 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. 5. Sorbonne University, ICM-Paris Brain Institute, INSERM, CNRS, APHP, Pitié Salpêtrière Hospital, Paris, France. 6. Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research (HIH), Center of Neurology, University of Tübingen, Tübingen, Germany. 7. German Center for Neurodegenerative Diseases (DZNE), University of Tübingen, Tübingen, Germany. 8. Koc University, School of Medicine, Suna and Inan Kirac Foundation, Istanbul, Turkey. 9. Department of Neurology, University Hospital Schleswig Holstein, Lübeck, Germany. 10. Institute of Neurogenetics, University of Lübeck, Lübeck, Germany. 11. Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tübingen, Germany. 12. Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Edegem, Belgium. 13. School of Medicine, Department of Neurology, Koc University, Istanbul, Turkey. 14. Department of Neurology, School of Medicine, Mersin University, Mersin, Turkey. 15. Department of Neurology, School of Medicine, Akdeniz University, Antalya, Turkey. 16. Clinic for Child Neurology and Psychiatry, University of Belgrade, Belgrade, Serbia. 17. Department of Neurology, University Hospital Essen, Essen, Germany. 18. Institute of Human Genetics, University Hospital Essen, Essen, Germany. 19. Department of Neurology, Friedrich-Baur-Institute, LMU Munich, Munich, Germany. 20. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Santiago de Compostela, Spain. 21. Neurogenetics Research Group, Instituto de Investigación Sanitaria (IDIS), Hospital Clínico Universitario, SERGAS, Santiago de Compostela, Spain. 22. Department of Neurosciences and Reproductive and Odontostomatological Sciences, Federico II University, Naples, Italy. 23. German Center for Neurodegenerative Diseases (DZNE), Munich, Germany. 24. Munich Cluster for Systems Neurology (SyNergy), Munich, Germany. 25. Unit of Neuromuscular and Neurodegenerative Disorders, Department of Neurosciences, Bambino Gesù Children's Hospital, Rome, Italy. 26. Molecular Medicine, IRCCS Fondazione Stella Maris, Pisa, Italy. 27. Peripheral Neuropathy Research Group, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium. 28. Centre for Rare Diseases, University of Tübingen, Tübingen, Germany. 29. Paris Sciences Lettres Research University, Ecole Pratique des Hautes Etudes, Paris, France.
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.
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.
Authors: Christian Gilissen; Jayne Y Hehir-Kwa; Djie Tjwan Thung; Maartje van de Vorst; Bregje W M van Bon; Marjolein H Willemsen; Michael Kwint; Irene M Janssen; Alexander Hoischen; Annette Schenck; Richard Leach; Robert Klein; Rick Tearle; Tan Bo; Rolph Pfundt; Helger G Yntema; Bert B A de Vries; Tjitske Kleefstra; Han G Brunner; Lisenka E L M Vissers; Joris A Veltman Journal: Nature Date: 2014-06-04 Impact factor: 49.962
Authors: Ana Victoria Marco Hernández; Alfonso Caro; Alejandro Montoya Filardi; Miguel Tomás Vila; Sandra Monfort; Beatriz Beseler Soto; Juan José Nieto-Barceló; Francisco Martínez Journal: Am J Med Genet A Date: 2021-09-30 Impact factor: 2.802
Authors: Ivan Iossifov; Brian J O'Roak; Stephan J Sanders; Michael Ronemus; Niklas Krumm; Dan Levy; Holly A Stessman; Kali T Witherspoon; Laura Vives; Karynne E Patterson; Joshua D Smith; Bryan Paeper; Deborah A Nickerson; Jeanselle Dea; Shan Dong; Luis E Gonzalez; Jeffrey D Mandell; Shrikant M Mane; Michael T Murtha; Catherine A Sullivan; Michael F Walker; Zainulabedin Waqar; Liping Wei; A Jeremy Willsey; Boris Yamrom; Yoon-ha Lee; Ewa Grabowska; Ertugrul Dalkic; Zihua Wang; Steven Marks; Peter Andrews; Anthony Leotta; Jude Kendall; Inessa Hakker; Julie Rosenbaum; Beicong Ma; Linda Rodgers; Jennifer Troge; Giuseppe Narzisi; Seungtai Yoon; Michael C Schatz; Kenny Ye; W Richard McCombie; Jay Shendure; Evan E Eichler; Matthew W State; Michael Wigler Journal: Nature Date: 2014-10-29 Impact factor: 69.504
Authors: Arkadiusz Miazek; Michał Zalas; Joanna Skrzymowska; Bryan A Bogin; Krzysztof Grzymajło; Tomasz M Goszczynski; Zachary A Levine; Jon S Morrow; Michael C Stankewich Journal: Sci Rep Date: 2021-03-31 Impact factor: 4.379
Authors: Lawrence A Kelley; Stefans Mezulis; Christopher M Yates; Mark N Wass; Michael J E Sternberg Journal: Nat Protoc Date: 2015-05-07 Impact factor: 13.491