Ataxie mit okulomotorischer Apraxie Typ 2: Charakterisierung des ...

Zusammenfassung 1
1. Zusammenfassung
1.1 Abstract
The recessively inherited ataxia-oculomotor apraxia type 2 (AOA2) is a neurodegenerative
disorder characterised by onset at juvenile to adolescent age, gait ataxia, cerebellar
atrophy, axonal sensorimotor neuropathy, oculomotor apraxia, and elevated serum AFP
level. AOA2 is caused by mutations within the senataxin gene (SETX) located on
chromosome 9q34. The SETX gene encodes a large 2677 amino acid protein, named
senataxin. The protein senataxin is the ortholog of the yeast RNA helicase Sen1p and
contains a DNA/RNA helicase domain at its C terminus and a putative protein interaction
domain at its N terminus. Senataxin is predicted to play a role in transcription and RNA
processing. Although senataxin possesses a putative DNA/RNA helicase domain, no
activity has yet been ascribed to the protein.
Mutation analyses in patients showing a clinical phenotype consistent with AOA2 revealed
homozygous or compound heterozygous mutations in the SETX gene for 12 of 79 patients
(~15%). A wide spectrum of different mutations could be detected: a nonsense mutation,
ten missense mutations, a splice site mutation, a 2 bp-deletion, two 4 bp-deletions, and four
gross gene rearrangements. Four of 19 mutations detected in the SETX gene are gross gene
rearrangements. The SETX gene harbours a high content of transposable elements (TE)
concerning the average of the human genome and therefore seems to be predisposed to
recombinogenic events. Three gross deletions were detected, which are predicted to arise
from TE-mediated homologous or non-homologous recombination. Furthermore, a ~1.3
kb-deletion generated by L1-endonuclease-dependent retrotransposition was identified.
This kind of mutation has not yet been described in AOA2 patients.
Additionally, eight patients showed a heterozygous missense exchange, whereas in the
samples of the other 59 patients no sequence variation could be detected in the SETX gene.
The AOA2 seems to be the most frequent form of known recessive ataxias after
Friedreich’s ataxia.