Abstract
Spinocerebellar ataxia type 28 (SCA28) is an autosomal dominant neurodegenerative disorder caused by missense AFG3L2 mutations. To examine the occurrence of SCA28 in the Czech Republic, we screened 288 unrelated ataxic patients with hereditary (N = 49) and sporadic or unknown (N = 239) form of ataxia for mutations in exons 15 and 16, the AFG3L2 mutation hotspots. A single significant variant, frameshift mutation c.1958dupT leading to a premature termination codon, was identified in a patient with slowly progressive speech and gait problems starting at the age of 68 years. Neurological examination showed cerebellar ataxia, mild Parkinsonian features with predominant bradykinesia, polyneuropathy of the lower limbs, and cognitive decline. However, other common SCA28 features like pyramidal tract signs (lower limb hyperreflexia, positive Babinski sign), ophthalmoparesis or ptosis were absent. The mutation was also found in a patient’s unaffected daughter in whom a targeted examination at 53 years of age revealed mild imbalance signs. RNA analysis showed a decreased ratio of the transcript from the mutated AFG3L2 allele relative to the normal transcript in the peripheral lymphocytes of both patients. The ratio was increased by puromycin treatment, indicating that the mutated transcript can be degraded via nonsense-mediated RNA decay. The causal link between the mutation and the phenotype of the patient is currently unclear but a pathogenic mechanism based on AFG3L2 haploinsufficiency rather than the usual dominant-negative effect of missense AFG3L2 mutations reported in SCA28, cannot be excluded.
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Acknowledgments
We thank the patients for their participation in the study, two anonymous reviewers for very valuable comments and Michal Krupka, Ph.D., for his help with Western blot analysis. This work was supported by grant NT-12221 and grant for conceptual development of research organization University Hospital Motol 00064203 from the Ministry of Health of the Czech Republic, and by grant IGA-LF_13_13 from the Internal grant agency of Palacky University.
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Musova, Z., Kaiserova, M., Kriegova, E. et al. A Novel Frameshift Mutation in the AFG3L2 Gene in a Patient with Spinocerebellar Ataxia. Cerebellum 13, 331–337 (2014). https://doi.org/10.1007/s12311-013-0538-z
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DOI: https://doi.org/10.1007/s12311-013-0538-z