Altered splicing of ATP6AP2 causes X-linked parkinsonism with spasticity (XPDS)

Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98195, USA.
Human Molecular Genetics (Impact Factor: 6.68). 04/2013; 22(16). DOI: 10.1093/hmg/ddt180
Source: PubMed

ABSTRACT We report a novel gene for a parkinsonian disorder. X-linked parkinsonism with spasticity (XPDS) presents either as typical adult onset Parkinson's disease or earlier onset spasticity followed by parkinsonism. We previously mapped the XPDS gene to a 28 Mb region on Xp11.2-X13.3. Exome sequencing of one affected individual identified five rare variants in this region, of which none was missense, nonsense or frame shift. Using patient-derived cells we tested the effect of these variants on expression/splicing of the relevant genes. A synonymous variant in ATP6P2, c.345C>T (p.S115S), markedly increased exon 4 skipping resulting in overexpression of a minor splice isoform that produces a protein with internal deletion of 32 aa in up to 50% of the total pool, with concomitant reduction of isoforms containing exon 4. ATP6P2 is an essential accessory component of the vacuolar ATPase required for lysosomal degradative functions and autophagy, a pathway frequently affected in Parkinson's disease. Reduction of the full-size ATP6AP2 transcript in XPDS cells and decreased level of ATP6AP2 protein in XPDS brain may compromise V-ATPase function, as seen with siRNA knockdown in HEK293 cells, and may ultimately be responsible for the pathology.Another synonymous mutation in the same exon, c.321C>T (p.D107D), has a similar molecular defect of exon inclusion and causes X-linked mental retardation Hedera type (MRXSH). Mutations in XPDS and MRXSH alter binding sites for different splicing factors, which may explain the marked differences in age of onset and manifestations.

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Jun 27, 2014