Brain Regional Differences in Hexanucleotide Repeat Length in X-Linked Dystonia-Parkinsonism Using Nanopore
Charles Jourdan Reyes1, Björn-Hergen Laabs1, Susen Schaake1
1Institute of Neurogenetics (C.J.R., S.S., T.L., R.A., A.R., K.G., D.A.-F., N.B., C.K., V.D., A.W., J.T.), University of Lübeck, and Institute of Medical Biometry and Statistics (B.-H.L., I.R.K.), University of Lübeck, Germany; Department of Neurosciences (R.D.J.), College of Medicine-Philippine General Hospital, University of the Philippines Manila; Department of Neurology and Psychiatry (R.L.R.), University of Santo Tomas Hospital, Manila, Philippines; Institute of Anatomy (I.W.), Department of Neurology (N.B.), and Lübeck Interdisciplinary Platform for Genome Analytics (V.D.), University of Lübeck, Germany.
Regional differences in hexanucleotide repeat numbers were found in brain tissues of patients with X-linked dystonia-parkinsonism (XDP). This repeat instability in specific brain regions may contribute to XDP disease manifestation.
Area of Science:
- Neurogenetics
- Molecular Neurology
Background:
- X-linked dystonia-parkinsonism (XDP) is a neurodegenerative disorder characterized by combined dystonia and parkinsonism.
- A (CCCTCT)n repeat expansion within a SINE-VNTR-Alu retrotransposon insertion in the TAF1 gene is the known cause of XDP.
Purpose of the Study:
- To investigate potential regional variations in hexanucleotide repeat length within the TAF1 gene in postmortem brain tissues of XDP patients.
- To explore the correlation between repeat instability and affected brain regions in XDP.
Main Methods:
- Genomic DNA extraction from blood and various postmortem brain regions (basal ganglia, cortex, cerebellum, midbrain, pituitary gland).
- Hexanucleotide repeat sizing using fragment analysis, small-pool PCR-based Southern blotting, and Oxford Nanopore sequencing.
Main Results:
- Significantly higher median hexanucleotide repeat numbers were observed in the basal ganglia and cerebellum compared to blood (p < 0.001).
- Increased repeat instability was also noted in the basal ganglia and cerebellum.
Conclusions:
- Somatic repeat instability appears to be more pronounced in brain regions critically affected in XDP.
- These findings suggest that regional repeat instability may play a significant role in the pathogenesis and phenotypic modification of XDP.
