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@ARTICLE{VandeVondel:164016,
author = {Van de Vondel, Liedewei and De Winter, Jonathan and Beijer,
Danique and Coarelli, Giulia and Wayand, Melanie and
Palvadeau, Robin and Pauly, Martje G and Klein, Katrin and
Rautenberg, Maren and Guillot-Noël, Léna and Deconinck,
Tine and Vural, Atay and Ertan, Sibel and Dogu, Okan and
Uysal, Hilmi and Brankovic, Vesna and Herzog, Rebecca and
Brice, Alexis and Dürr, Alexandra and Klebe, Stephan and
Stock, Friedrich and Bischoff, Almut Turid and Rattay, Tim W
and Sobrido, María-Jesús and De Michele, Giovanna and De
Jonghe, Peter and Klopstock, Thomas and Lohmann, Katja and
Zanni, Ginevra and Santorelli, Filippo M and Timmerman,
Vincent and Haack, Tobias B and Züchner, Stephan and
Schüle, Rebecca and Stevanin, Giovanni and Synofzik,
Matthis and Basak, A Nazli and Baets, Jonathan},
collaboration = {Consortium, PREPARE},
title = {{D}e {N}ovo and {D}ominantly {I}nherited {SPTAN}1
{M}utations {C}ause {S}pastic {P}araplegia and {C}erebellar
{A}taxia.},
journal = {Movement disorders},
volume = {37},
number = {6},
issn = {0885-3185},
address = {New York, NY},
publisher = {Wiley},
reportid = {DZNE-2022-00679},
pages = {1175-1186},
year = {2022},
abstract = {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.},
keywords = {Carrier Proteins: genetics / Cerebellar Ataxia: genetics /
Humans / Intellectual Disability: genetics / Microfilament
Proteins: genetics / Mutation: genetics / Paraplegia:
genetics / Pedigree / Phenotype / Spastic Paraplegia,
Hereditary: genetics / Spectrin: genetics / ataxia (Other) /
next-generation sequencing (Other) / rare diseases (Other) /
spastic paraplegia (Other) / spectrin (Other)},
cin = {AG Gasser / Core ICRU / Clinical Research (Munich)},
ddc = {610},
cid = {I:(DE-2719)1210000 / I:(DE-2719)1240005 /
I:(DE-2719)1111015},
pnm = {353 - Clinical and Health Care Research (POF4-353)},
pid = {G:(DE-HGF)POF4-353},
typ = {PUB:(DE-HGF)16},
pmc = {pmc:PMC9232883},
pubmed = {pmid:35150594},
doi = {10.1002/mds.28959},
url = {https://pub.dzne.de/record/164016},
}