New spinocerebellar ataxia subtype caused by SAMD9L mutation triggering mitochondrial dysregulation (SCA49)

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  • dc.contributor.author Corral Juan, Marc
  • dc.contributor.author Casquero, Pilar
  • dc.contributor.author Giraldo-Restrepo, Natalia
  • dc.contributor.author Laurie, Steven, 1973-
  • dc.contributor.author Martinez-Piñeiro, Alicia
  • dc.contributor.author Mateo-Montero, Raidili Cristina
  • dc.contributor.author Ispierto, Lourdes
  • dc.contributor.author Vilas, Dolores
  • dc.contributor.author Tolosa, Eduard
  • dc.contributor.author Volpini, Victor
  • dc.contributor.author Alvarez-Ramo, Ramiro
  • dc.contributor.author Sánchez, Ivelisse
  • dc.contributor.author Matilla Dueñas, Antoni
  • dc.date.accessioned 2022-05-24T10:33:26Z
  • dc.date.available 2022-05-24T10:33:26Z
  • dc.date.issued 2022
  • dc.description.abstract Spinocerebellar ataxias consist of a highly heterogeneous group of inherited movement disorders clinically characterized by progressive cerebellar ataxia variably associated with additional distinctive clinical signs. The genetic heterogeneity is evidenced by the myriad of associated genes and underlying genetic defects identified. In this study, we describe a new spinocerebellar ataxia subtype in nine members of a Spanish five-generation family from Menorca with affected individuals variably presenting with ataxia, nystagmus, dysarthria, polyneuropathy, pyramidal signs, cerebellar atrophy and distinctive cerebral demyelination. Affected individuals presented with horizontal and vertical gaze-evoked nystagmus and hyperreflexia as initial clinical signs, and a variable age of onset ranging from 12 to 60 years. Neurophysiological studies showed moderate axonal sensory polyneuropathy with altered sympathetic skin response predominantly in the lower limbs. We identified the c.1877C > T (p.Ser626Leu) pathogenic variant within the SAMD9L gene as the disease causative genetic defect with a significant log-odds score (Z max = 3.43; θ = 0.00; P < 3.53 × 10-5). We demonstrate the mitochondrial location of human SAMD9L protein, and its decreased levels in patients' fibroblasts in addition to mitochondrial perturbations. Furthermore, mutant SAMD9L in zebrafish impaired mobility and vestibular/sensory functions. This study describes a novel spinocerebellar ataxia subtype caused by SAMD9L mutation, SCA49, which triggers mitochondrial alterations pointing to a role of SAMD9L in neurological motor and sensory functions.
  • dc.description.sponsorship The research of this work was funded by the Instituto de Salud Carlos III with grants PI14/00136 (to A.M.-D.), PI17/00534 (to A.M.-D. and I.S.) and PI14/01159 (to V.V.). Antoni Matilla Dueñas was a Miguel Servet Investigator in Neuroscience supported by the Instituto de Salud Carlos III (ISCIII; CP14/00029)
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Corral-Juan M, Casquero P, Giraldo-Restrepo N, Laurie E, Martinez-Piñeiro A, Mateo-Montero RC et al. New spinocerebellar ataxia subtype caused by SAMD9L mutation triggering mitochondrial dysregulation (SCA49). Brain Commun. 2022 Feb 10;4(2):fcac030. DOI:10.1093/braincomms/fcac030
  • dc.identifier.doi http://dx.doi.org/10.1093/braincomms/fcac030
  • dc.identifier.issn 2632-1297
  • dc.identifier.uri http://hdl.handle.net/10230/53229
  • dc.language.iso eng
  • dc.publisher Oxford University Press
  • dc.rights © Marc Corral-Juan et al. 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri https://creativecommons.org/licenses/by/4.0/
  • dc.subject.other Atàxia espinocerebel·losa
  • dc.subject.other Mitocondris
  • dc.subject.other Genètica
  • dc.title New spinocerebellar ataxia subtype caused by SAMD9L mutation triggering mitochondrial dysregulation (SCA49)
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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