ClinVar

In affected members of a family with X-linked parkinsonism with spasticity (XPDS; 300911), originally reported by Poorkaj et al. (2010), Korvatska et al. (2013) identified a c.345C-T transition in exon 4 of the ATP6AP2 gene, predicted to result in a synonymous ser115-to-ser (S115S) substitution. Studies of patient-derived cells showed that the c.345C-T mutation markedly increased the skipping of exon 4, resulting in significant overexpression (about 50%) of a 150-bp minor splice isoform that produces a protein with internal deletion of 32 amino acids. The increase in this abnormal isoform was associated with a reduction in normal isoforms containing exon 4. Molecular modeling predicted that the mutation creates a new splice silencer site. The mutation, which was found by X-chromosome exome sequencing and confirmed by Sanger sequencing, segregated with the phenotype. It was not found in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases. All patients developed parkinsonism as adults, but 3 developed spasticity before the onset of parkinsonism. Carrier females were unaffected. Postmortem brain tissue from 1 affected individual showed decreased ATP6AP2 immunostaining in the frontal cortex and striatum. In addition, there was massive accumulation of SQSTM1 (601530) in the striatum, suggesting impaired autophagy and a defect in lysosome-mediated protein degradation.