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000164016 1001_ $$00000-0003-2214-5908$$aVan de Vondel, Liedewei$$b0
000164016 245__ $$aDe Novo and Dominantly Inherited SPTAN1 Mutations Cause Spastic Paraplegia and Cerebellar Ataxia.
000164016 260__ $$aNew York, NY$$bWiley$$c2022
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000164016 520__ $$aPathogenic 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.
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000164016 650_7 $$2Other$$aataxia
000164016 650_7 $$2Other$$anext-generation sequencing
000164016 650_7 $$2Other$$arare diseases
000164016 650_7 $$2Other$$aspastic paraplegia
000164016 650_7 $$2Other$$aspectrin
000164016 650_2 $$2MeSH$$aCarrier Proteins: genetics
000164016 650_2 $$2MeSH$$aCerebellar Ataxia: genetics
000164016 650_2 $$2MeSH$$aHumans
000164016 650_2 $$2MeSH$$aIntellectual Disability: genetics
000164016 650_2 $$2MeSH$$aMicrofilament Proteins: genetics
000164016 650_2 $$2MeSH$$aMutation: genetics
000164016 650_2 $$2MeSH$$aParaplegia: genetics
000164016 650_2 $$2MeSH$$aPedigree
000164016 650_2 $$2MeSH$$aPhenotype
000164016 650_2 $$2MeSH$$aSpastic Paraplegia, Hereditary: genetics
000164016 650_2 $$2MeSH$$aSpectrin: genetics
000164016 7001_ $$aDe Winter, Jonathan$$b1
000164016 7001_ $$aBeijer, Danique$$b2
000164016 7001_ $$aCoarelli, Giulia$$b3
000164016 7001_ $$0P:(DE-2719)9001023$$aWayand, Melanie$$b4$$udzne
000164016 7001_ $$00000-0002-4730-6598$$aPalvadeau, Robin$$b5
000164016 7001_ $$00000-0002-7794-0282$$aPauly, Martje G$$b6
000164016 7001_ $$aKlein, Katrin$$b7
000164016 7001_ $$aRautenberg, Maren$$b8
000164016 7001_ $$aGuillot-Noël, Léna$$b9
000164016 7001_ $$aDeconinck, Tine$$b10
000164016 7001_ $$aVural, Atay$$b11
000164016 7001_ $$aErtan, Sibel$$b12
000164016 7001_ $$aDogu, Okan$$b13
000164016 7001_ $$00000-0002-6063-377X$$aUysal, Hilmi$$b14
000164016 7001_ $$aBrankovic, Vesna$$b15
000164016 7001_ $$00000-0002-5906-5947$$aHerzog, Rebecca$$b16
000164016 7001_ $$aBrice, Alexis$$b17
000164016 7001_ $$0P:(DE-2719)9000429$$aDürr, Alexandra$$b18$$udzne
000164016 7001_ $$aKlebe, Stephan$$b19
000164016 7001_ $$aStock, Friedrich$$b20
000164016 7001_ $$aBischoff, Almut Turid$$b21
000164016 7001_ $$0P:(DE-2719)2811827$$aRattay, Tim W$$b22$$udzne
000164016 7001_ $$00000-0002-6411-1020$$aSobrido, María-Jesús$$b23
000164016 7001_ $$aDe Michele, Giovanna$$b24
000164016 7001_ $$aDe Jonghe, Peter$$b25
000164016 7001_ $$0P:(DE-2719)2810704$$aKlopstock, Thomas$$b26$$udzne
000164016 7001_ $$0P:(DE-2719)9000191$$aLohmann, Katja$$b27$$udzne
000164016 7001_ $$aZanni, Ginevra$$b28
000164016 7001_ $$aSantorelli, Filippo M$$b29
000164016 7001_ $$aTimmerman, Vincent$$b30
000164016 7001_ $$aHaack, Tobias B$$b31
000164016 7001_ $$aZüchner, Stephan$$b32
000164016 7001_ $$aConsortium, PREPARE$$b33$$eCollaboration Author
000164016 7001_ $$0P:(DE-2719)2812018$$aSchüle, Rebecca$$b34$$udzne
000164016 7001_ $$aStevanin, Giovanni$$b35
000164016 7001_ $$0P:(DE-2719)2811275$$aSynofzik, Matthis$$b36$$udzne
000164016 7001_ $$00000-0001-6977-2517$$aBasak, A Nazli$$b37
000164016 7001_ $$aBaets, Jonathan$$b38
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