Skip to main content
SpringerLink
Log in

Aberrant Splicing Caused by a Novel VPS16 Variant Linked to Dystonia Type 30

  • Short Communication
  • Published:
neurogenetics Aims and scope Submit manuscript

Abstract

Dystonia is a hyperkinetic movement disorder characterized by sustained or intermittent involuntary muscle contractions, causing abnormal postures and/or repetitive movements. In this report, we identified a novel heterozygous splice-site variant in VPS16 (NM_022575.4:c.240+3G>C) in a patient with cervical and upper limb dystonia without other neurological or extra-neurological features. Analysis of patient’s blood mRNA showed disruption of exon 3/intron 3 donor splice-site, leading to exon 3 skipping, which predictably results in a frameshift [p.(Ala48Valfs*14)]. Despite the scarcity of splice-affecting variants described in VPS16-related dystonia, our report contributes with the first fully characterized variant at the mRNA level.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Data availability

Research data have not been archived at a public repository but are available from the corresponding author upon reasonable request.

References

  1. Albanese A, Bhatia K, Bressman SB et al (2013) Phenomenology and classification of dystonia: a consensus update. Mov Disord 28:863–873. https://doi.org/10.1002/mds.25475

    Article  PubMed  PubMed Central  Google Scholar 

  2. Jinnah HA, Teller JK, Galpern WR (2015) Recent developments in dystonia. Curr Opin Neurol 28:400–405. https://doi.org/10.1097/WCO.0000000000000213

    Article  PubMed  PubMed Central  Google Scholar 

  3. Powis Z, Towne MC, Hagman KDF et al (2020) Clinical diagnostic exome sequencing in dystonia: genetic testing challenges for complex conditions. Clin Genet 97:305–311. https://doi.org/10.1111/cge.13657

    Article  CAS  PubMed  Google Scholar 

  4. Zech M, Jech R, Boesch S et al (2020) Monogenic variants in dystonia: an exome-wide sequencing study. Lancet Neurol 19:908–918. https://doi.org/10.1016/S1474-4422(20)30312-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Park J, Reilaender A, Petry-Schmelzer JN et al (2022) Transcript-specific loss-of-function variants in VPS16 are enriched in patients with dystonia. Neurol Genet 8:e644. https://doi.org/10.1212/nxg.0000000000000644

    Article  PubMed  Google Scholar 

  6. Cai X, Chen X, Wu S et al (2016) Homozygous mutation of VPS16 gene is responsible for an autosomal recessive adolescent-onset primary dystonia. Sci Rep 6:1–10. https://doi.org/10.1038/srep25834

    Article  CAS  Google Scholar 

  7. Steel D, Zech M, Zhao C et al (2020) Loss-of-function variants in HOPS complex genes VPS16 and VPS41 cause early onset dystonia associated with lysosomal abnormalities. Ann Neurol 88:867–877. https://doi.org/10.1002/ana.25879

    Article  CAS  PubMed  Google Scholar 

  8. Yao LX, Wang L, Guo Y, Hua WX (2021) Mutations in the VPS16 gene in 56 early-onset dystonia patients. Mov Disord 36:780–781. https://doi.org/10.1002/mds.28540

    Article  Google Scholar 

  9. Ostrozovicova M, Jech R, Steel D et al (2021) A recurrent VPS16 p.Arg187* nonsense variant in early-onset generalized dystonia. Mov Disord 36:1984–1985. https://doi.org/10.1002/mds.28647

    Article  CAS  PubMed  Google Scholar 

  10. Pott H, Brüggemann N, Reese R et al (2021) Truncating VPS16 mutations are rare in early onset dystonia. Ann Neurol 89:625–626. https://doi.org/10.1002/ana.25990

    Article  CAS  PubMed  Google Scholar 

  11. Li L-X, Jiang L-T, Liu Y et al (2021) Mutation screening of VPS16 gene in patients with isolated dystonia. Parkinsonism Relat Disord 83:63–65. https://doi.org/10.1016/j.parkreldis.2020.12.014

    Article  CAS  PubMed  Google Scholar 

  12. Huizing M, Didier A, Walenta J et al (2001) Molecular cloning and characterization of human VPS18, VPS 11, VPS16, and VPS33. Gene 264:241–247. https://doi.org/10.1016/s0378-1119(01)00333-x

    Article  CAS  PubMed  Google Scholar 

  13. Sofou K, Meier K, Sanderson LE et al (2021) Bi-allelic VPS16 variants limit HOPS/CORVET levels and cause a mucopolysaccharidosis-like disease. EMBO Mol Med 13:1–21. https://doi.org/10.15252/emmm.202013376

    Article  CAS  Google Scholar 

  14. Yıldız Y, Koşukcu C, Aygün D et al (2021) Homozygous missense VPS16 variant is associated with a novel disease, resembling mucopolysaccharidosis-plus syndrome in two siblings. Clin Genet 100:308–317. https://doi.org/10.1111/cge.14002

    Article  CAS  PubMed  Google Scholar 

  15. Gegg ME, Menozzi E, Schapira AHV (2022) Glucocerebrosidase-associated Parkinson disease: pathogenic mechanisms and potential drug treatments. Neurobiol Dis 166:105663. https://doi.org/10.1016/j.nbd.2022.105663

    Article  CAS  PubMed  Google Scholar 

  16. Lohmann K, Klein C (2013) Genetics of dystonia: what’s known? What’s new? What’s next? Mov Disord 28:899–905. https://doi.org/10.1002/mds.25536

    Article  CAS  PubMed  Google Scholar 

  17. Müller B, Hedrich K, Kock N et al (2002) Evidence that paternal expression of the ε-sarcoglycan gene accounts for reduced penetrance in myoclonus-dystonia. Am J Hum Genet 71:1303–1311. https://doi.org/10.1086/344531

    Article  PubMed  PubMed Central  Google Scholar 

  18. Wang G-S, Cooper TA (2007) Splicing in disease: disruption of the splicing code and the decoding machinery. Nat Rev Genet 8:749–761. https://doi.org/10.1038/nrg2164

    Article  CAS  PubMed  Google Scholar 

  19. Wartosch L, Günesdogan U, Graham SC, Luzio JP (2015) Recruitment of VPS33A to HOPS by VPS16 is required for lysosome fusion with endosomes and autophagosomes. Traffic 16:727–742. https://doi.org/10.1111/tra.12283

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Monfrini E, Zech M, Steel D et al (2021) HOPS-associated neurological disorders (HOPSANDs): linking endolysosomal dysfunction to the pathogenesis of dystonia. Brain 144:2610–2615. https://doi.org/10.1093/brain/awab161

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We sincerely thank the patient for the participation in this study.

Funding

M. S. acknowledges funding from FCT-Fundação para a Ciência e a Tecnologia, I.P. through the program DL 57/2016 - Norma Transitória.

Author information

Authors and Affiliations

  1. UnIGENe, IBMC-Institute for Molecular and Cell Biology, i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, R. Alfredo Allen 208, 4200-135, Porto, Portugal

    Mariana Santos

  2. Department of Neurology, Centro Hospitalar Universitário de São João, and Faculty of Medicine University of Porto, Porto, Portugal

    João Massano

  3. CGPP-Center for Predictive and Preventive Genetics, IBMC-Institute for Molecular and Cell Biology, i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal

    Alexandra Manuel Lopes, Ana Filipa Brandão, João Parente Freixo & Jorge Oliveira

Authors
  1. Mariana Santos
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. João Massano
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alexandra Manuel Lopes
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ana Filipa Brandão
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. João Parente Freixo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jorge Oliveira
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

M.S. performed gene expression experiments and prepared the figure and table. J.M. identified the patient and performed clinical data collection. Initial genetic and bioinformatics analysis was performed by A.M.L. and A.F.B., and results were validated by J.O. The work was supervised by J.P.F and J.O. The manuscript was initially drafted by M.S. and J.M. All authors critically revised the manuscript and approved the final version.

Corresponding author

Correspondence to Mariana Santos.

Ethics declarations

Ethical approval

The study was conducted in accordance with the Declaration of Helsinki. Written and verbal informed consent was obtained from the patient. The authors confirm that the approval of the institutional review board is not required for this work.

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

ESM 1

(DOCX 21 kb)

ESM 2

(PDF 175 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Santos, M., Massano, J., Lopes, A.M. et al. Aberrant Splicing Caused by a Novel VPS16 Variant Linked to Dystonia Type 30. Neurogenetics 24, 215–218 (2023). https://doi.org/10.1007/s10048-023-00720-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10048-023-00720-0

Keywords

Search

Navigation