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

摘要

Wereport anovelgeneforaparkinsonian disorder. X-linkedparkinsonism 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 patientderived cells, we tested the effect of these variants on expression/splicing of the relevant genes. Asynonymous variant inATP6AP2, c.345CT(p.S115S),markedly increasedexon4 skipping, resulting in the overexpression of a minor splice isoform that produces a protein with internal deletion of 32 amino acids in up to 50% of the total pool, with concomitant reduction of isoforms containing exon 4.ATP6AP2 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.321CT (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.