PUBLICATION
New spinocerebellar ataxia subtype caused by SAMD9L mutation triggering mitochondrial dysregulation (SCA49)
- Authors
- Corral-Juan, M., Casquero, P., Giraldo-Restrepo, N., Laurie, S., Martinez-Piñeiro, A., Mateo-Montero, R.C., Ispierto, L., Vilas, D., Tolosa, E., Volpini, V., Alvarez-Ramo, R., Sánchez, I., Matilla-Dueñas, A.
- ID
- ZDB-PUB-220323-11
- Date
- 2022
- Source
- Brain communications 4: fcac030 (Journal)
- Registered Authors
- Keywords
- SAMD9L, SCA49, mitochondria, spinocerebellar ataxia, zebrafish
- MeSH Terms
- none
- PubMed
- 35310830 Full text @ Brain Commun
Citation
Corral-Juan, M., Casquero, P., Giraldo-Restrepo, N., Laurie, S., Martinez-Piñeiro, A., Mateo-Montero, R.C., Ispierto, L., Vilas, D., Tolosa, E., Volpini, V., Alvarez-Ramo, R., Sánchez, I., Matilla-Dueñas, A. (2022) New spinocerebellar ataxia subtype caused by SAMD9L mutation triggering mitochondrial dysregulation (SCA49). Brain communications. 4:fcac030.
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 (Zmax = 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping