title: A novel frameshift mutation in the AFG3L2 gene in a patient with spinocerebellar ataxia.
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.
authors.affiliation: Department of Biology and Medical Genetics, Charles University 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic, zuzana.musova@fnmotol.cz.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Musova
authors.forename: Michaela
authors.initials: M
authors.lastname: Kaiserova
authors.forename: Eva
authors.initials: E
authors.lastname: Kriegova
authors.forename: Regina
authors.initials: R
authors.lastname: Fillerova
authors.forename: Peter
authors.initials: P
authors.lastname: Vasovcak
authors.forename: Alena
authors.initials: A
authors.lastname: Santava
authors.forename: Katerina
authors.initials: K
authors.lastname: Mensikova
authors.forename: Alena
authors.initials: A
authors.lastname: Zumrova
authors.forename: Anna
authors.initials: A
authors.lastname: Krepelova
authors.forename: Zdenek
authors.initials: Z
authors.lastname: Sedlacek
authors.forename: Petr
authors.initials: P
authors.lastname: Kanovsky
mesh_terms: D049069:ATP-Dependent Proteases / Q000235:genetics*; D000074183:ATPases Associated with Diverse Cellular Activities; D000368:Aged; D018153:Czech Republic; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D009886:Ophthalmoplegia / Q000235:genetics; D010641:Phenotype; D020754:Spinocerebellar Ataxias / Q000175:diagnosis / Q000235:genetics* / Q000151:congenital; D013132:Spinocerebellar Degenerations / Q000235:genetics*
chemical_list: D049069:ATP-Dependent Proteases; C120699:AFG3L2 protein, human; D000074183:ATPases Associated with Diverse Cellular Activities