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Cited by 140Parkinson's Disease Mechanisms and TreatmentsRNA Research and SplicingHereditary Neurological Disorders

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

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Korvatska, Olena, Strand, Nicholas S., Berndt, Jason D., Strovas, Tim, Chen, Dong-Hui, Leverenz, James B., Kiianitsa, Konstantin, Mata, Ignacio F. +11 more·2013·Human Molecular Genetics
DOI 10.1093/hmg/ddt180PMC PMC3723311
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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 ATP6AP2, c.345C>T (p.S115S), markedly increased exon 4 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.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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  • The associated childhood disorders highlight the variety of processes in which the lysosome is involved, from myelination (TMEM106B, hypomyelinating leukodystrophy) to cell growth (TSC1, tuberous sclerosis) and bone resorption (SQSTM1).

    “The associated childhood disorders highlight the variety of processes in which the lysosome is involved, from myelination (TMEM106B, hypomyelinating leukodystrophy) to cell growth (TSC1, tuberous sclerosis) and bone resorption (SQSTM1).89–91”

    From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [90]

    The Discussion and Results discuss p62/SQSTM1 as a marker of impaired autophagy in XPDS, not as a cause of a childhood bone-resorption disorder. Searches for bone resorption and for the named myelination and cell-growth disorders found no passage in our copy addressing those associations; no page numbers were provided. (LLM, conf=0.74)

    Experimental — accuracy not yet measured

  • TSC1 mutations increase the risk of FTD with tau accumulation.

    “In recent years, we showed that TSC1 mutations also increase the risk of FTD with tau accumulation.90,140”

    From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [90]

    The Discussion describes an ATP6AP2 mutation causing X-linked parkinsonism with spasticity and reports tau deposits in an XPDS brain. A search for TSC1 mutations and frontotemporal dementia found no passage in our copy addressing whether TSC1 increases the risk of FTD with tau accumulation; page numbers were not available. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

  • Individuals with TSC1 mutations accumulate tau inclusions with abnormal acetylation distinct from the tau inclusions observed in AD and FTLD.

    “Surprisingly, these individuals accumulate tau inclusions with abnormal acetylation distinct from the tau inclusions observed in AD and FTLD.90,140”

    From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [90]

    The Discussion reports pathological tau deposits in the striatum of an XPDS brain with ATP6AP2 deficiency, not in individuals with TSC1 mutations. Searches for TSC1, acetylated tau, and comparisons with AD or FTLD found no passage addressing the attributed claim. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

  • There are mTORC1-independent mechanisms of tau accumulation in TSC1-mediated tauopathy.

    “Of note, inhibiting mTORC1 does not fully rescue tau degradation in TSC1 haploinsufficient iNeurons, suggesting that there are also mTORC1-independent mechanisms of tau accumulation in TSC1-mediated tauopathy.90”

    From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [90]

    The Discussion describes ATP6AP2 deficiency, tau deposits, and impaired protein degradation in XPDS brain; the Results report impaired autophagy in the XPDS striatum. Searches for TSC1 haploinsufficient iNeurons, mTORC1 inhibition, and mTORC1-independent tau accumulation found no passage addressing those claims in this paper. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

  • Reducing tau acetylation restores its degradation through CMA.

    “Reducing tau acetylation restores its degradation through CMA (Figure 5).90,147”

    From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [90]

    The Results describe impaired autophagy and lysosomal clearance with ATP6AP2 deficiency, and the Discussion notes pathological tau deposits in XPDS brain (pages not provided). Searches for tau acetylation, deacetylation, and chaperone-mediated autophagy found no passage saying that reducing tau acetylation restores its degradation through CMA. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

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Authors
Korvatska, O., Strand, N. S., Berndt, J. D., Strovas, T., Chen, D.-H., Leverenz, J. B., Kiianitsa, K., Mata, I. F., Karakoc, E., Greenup, J. L., Bonkowski, E., Chuang, J., Moon, R. T., Eichler, E. E., Nickerson, D. A., Zabetian, C. P., Kraemer, B. C., Bird, T. D., & Raskind, W. H.
Affiliations
  • University of Washington (US)
  • Geriatric Research Education and Clinical Center (US)
  • Howard Hughes Medical Institute (US)
  • United States Department of Veterans Affairs (US)
ORCID
Venue
Human Molecular Genetics
Publisher
Oxford University Press (OUP)
Published
2013-04-16
Volume
22
Issue
16
Pages
3259-3268
ISSN
  • 0964-6906 (ISSN-L)
  • 1460-2083
DOI
10.1093/hmg/ddt180
PMC
PMC3723311
OpenAlex
W2101004718
Cited by
140
References
2
Citations by year
2026: 5 · 2025: 7 · 2024: 11 · 2023: 9 · 2022: 14 · 2021: 17 · 2020: 16 · 2019: 7 · 2018: 12 · 2017: 11 · 2016: 9 · 2015: 17 · 2014: 2 · 2013: 3
FWCI
6.56
Type
journal article
Language
en
Open access
Locations
  • Human Molecular Genetics (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • U.S. Department of Veterans Affairs (I01 BX000531)
  • Women's Health Initiative
  • National Institutes of Health
  • Geriatric Research Education and Clinical Center
  • National Institute on Aging (P50AG005136)
  • National Heart, Lung, and Blood Institute (HL-102924, HL-102925, HL 1029230, HL 103010, HL-102926)
  • National Human Genome Research Institute (RC2HG005608)
  • National Institute of General Medical Sciences (T32 GM00727, P01GM081619)
  • National Institute of Neurological Disorders and Stroke (P50NS062684, R01NS065070, R01NS069719, R01NS064131)
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
Keywords
ATP6AP2, exon skipping, alternative splicing, synonymous mutations, Parkinson's disease, spasticity, vacuolar ATPase, lysosomal degradation, autophagy, X-linked intellectual disability, splicing factors
MeSH terms
Prorenin Receptor, Aged, Binding Sites, Cells, Cultured, Female, Gene Expression Regulation, Humans, Genetic Linkage, Male, Muscle Spasticity, Receptors, Cell Surface, Genetic Variation, Frameshift Mutation, Sequence Analysis, RNA, Codon, Nonsense, Mutation, Missense, Parkinsonian Disorders, Vacuolar Proton-Translocating ATPases, X-Linked Intellectual Disability, Mental Retardation, X-Linked, Genetic Diseases, X-Linked, Chromosomes, Human, X, Gene Knockdown Techniques, HEK293 Cells, Exome

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