PUBLICATION
SCAR32: Functional characterization and expansion of the clinical-genetic spectrum
- Authors
- Naef, V., Lieto, M., Satolli, S., De Micco, R., Troisi, M., Pasquariello, R., Doccini, S., Privitera, F., Filla, A., Tessitore, A., Santorelli, F.M.
- ID
- ZDB-PUB-240606-5
- Date
- 2024
- Source
- Annals of clinical and translational neurology 11(7): 1879-1886 (Journal)
- Registered Authors
- Naef, Valentina, Santorelli, Filippo Maria
- Keywords
- none
- MeSH Terms
-
- Animals
- Fibroblasts
- Humans
- Male
- Mutation
- Spinocerebellar Ataxias/congenital
- Spinocerebellar Ataxias/genetics
- Young Adult
- Zebrafish*
- PubMed
- 38837640 Full text @ Ann Clin Transl Neurol
Citation
Naef, V., Lieto, M., Satolli, S., De Micco, R., Troisi, M., Pasquariello, R., Doccini, S., Privitera, F., Filla, A., Tessitore, A., Santorelli, F.M. (2024) SCAR32: Functional characterization and expansion of the clinical-genetic spectrum. Annals of clinical and translational neurology. 11(7):1879-1886.
Abstract
Objective Biallelic mutations in PRDX3 have been linked to autosomal recessive spinocerebellar ataxia type 32. In this study, which aims to contribute to the growing body of knowledge on this rare disease, we identified two unrelated patients with mutations in PRDX3. We explored the impact of PRDX3 mutation in patient skin fibroblasts and the role of the gene in neurodevelopment.
Methods We performed trio exome sequencing that identified mutations in PRDX3 in two unrelated patients. We also performed functional studies in patient skin fibroblasts and generated a "crispant" zebrafish (Danio rerio) model to investigate the role of the gene during nervous system development.
Results Our study reports two additional patients. Patient 1 is a 19-year-old male who showed a novel homozygous c.525_535delGTTAGAAGGTT (p. Leu176TrpfsTer11) mutation as the genetic cause of cerebellar ataxia. Patient 2 is a 20-year-old male who was found to present the known c.425C>G/p. Ala142Gly variant in compound heterozygosity with the p. Leu176TrpfsTer11 one. While the fibroblast model failed to recapitulate the pathological features associated with PRDX3 loss of function, our functional characterization of the prdx3 zebrafish model revealed motor defects, increased susceptibility to reactive oxygen species-triggered apoptosis, and an impaired oxygen consumption rate.
Conclusions We identified a new variant, thereby expanding the genetic spectrum of PRDX3-related disease. We developed a novel zebrafish model to investigate the consequences of prdx3 depletion on neurodevelopment and thus offered a potential new tool for identifying new treatment opportunities.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping