TY  - JOUR
AU  - Van de Vondel, Liedewei
AU  - De Winter, Jonathan
AU  - Beijer, Danique
AU  - Coarelli, Giulia
AU  - Wayand, Melanie
AU  - Palvadeau, Robin
AU  - Pauly, Martje G
AU  - Klein, Katrin
AU  - Rautenberg, Maren
AU  - Guillot-Noël, Léna
AU  - Deconinck, Tine
AU  - Vural, Atay
AU  - Ertan, Sibel
AU  - Dogu, Okan
AU  - Uysal, Hilmi
AU  - Brankovic, Vesna
AU  - Herzog, Rebecca
AU  - Brice, Alexis
AU  - Dürr, Alexandra
AU  - Klebe, Stephan
AU  - Stock, Friedrich
AU  - Bischoff, Almut Turid
AU  - Rattay, Tim W
AU  - Sobrido, María-Jesús
AU  - De Michele, Giovanna
AU  - De Jonghe, Peter
AU  - Klopstock, Thomas
AU  - Lohmann, Katja
AU  - Zanni, Ginevra
AU  - Santorelli, Filippo M
AU  - Timmerman, Vincent
AU  - Haack, Tobias B
AU  - Züchner, Stephan
AU  - Schüle, Rebecca
AU  - Stevanin, Giovanni
AU  - Synofzik, Matthis
AU  - Basak, A Nazli
AU  - Baets, Jonathan
TI  - De Novo and Dominantly Inherited SPTAN1 Mutations Cause Spastic Paraplegia and Cerebellar Ataxia.
JO  - Movement disorders
VL  - 37
IS  - 6
SN  - 0885-3185
CY  - New York, NY
PB  - Wiley
M1  - DZNE-2022-00679
SP  - 1175-1186
PY  - 2022
AB  - 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.
KW  - Carrier Proteins: genetics
KW  - Cerebellar Ataxia: genetics
KW  - Humans
KW  - Intellectual Disability: genetics
KW  - Microfilament Proteins: genetics
KW  - Mutation: genetics
KW  - Paraplegia: genetics
KW  - Pedigree
KW  - Phenotype
KW  - Spastic Paraplegia, Hereditary: genetics
KW  - Spectrin: genetics
KW  - ataxia (Other)
KW  - next-generation sequencing (Other)
KW  - rare diseases (Other)
KW  - spastic paraplegia (Other)
KW  - spectrin (Other)
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC9232883
C6  - pmid:35150594
DO  - DOI:10.1002/mds.28959
UR  - https://pub.dzne.de/record/164016
ER  -