Comprehensive analysis across SMN2 excludes DNA methylation as an epigenetic biomarker for spinal muscular atrophy
Spinal muscular atrophy (SMA) is a severe neurodegenerative disease caused by defects in the <i>survival motor neuron 1</i> (<i>SMN1</i>) gene. Although disease severity partially correlates with <i>SMN2</i> copy number, significant variability in disease severity and treatment response remains unexplained, prompting a search for additional biomarkers. Using native, long-read nanopore and targeted short-read bisulfite sequencing, we analyzed methylation patterns across the 30 kb <i>SMN2</i> gene. Our long-read analysis of 29 SMA patients identified tissue-specific variation in <i>SMN2</i> intronic regions and the 3'UTR. Further analysis of blood-derived DNA of 365 SMA patients identified no association between <i>SMN2</i> methylation and disease severity or treatment response, excluding blood-derived DNA methylation as a predictive biomarker. However, we discovered significant age-associated variation in <i>SMN2</i> methylation in intron 1 and the 3'UTR, suggesting a possible role in modifying SMN expression during development and aging. This study provides a framework for detailed methylation analysis in complex genetic regions.
Authors
- Jared W Green
- W. Ludo van der Pol (ORCID: https://orcid.org/0000-0002-8970-2740)
- Maria M Zwartkruis (ORCID: https://orcid.org/0000-0002-8868-7155)
- Martin Elferink (ORCID: https://orcid.org/0000-0002-7940-7422)
- Gijs W. van Haaften
- Hanneke W. M. van Deutekom (ORCID: https://orcid.org/0000-0002-2429-1098)
- Ilaria Signoria (ORCID: https://orcid.org/0000-0002-8314-651X)
- Ewout J. N. Groen (ORCID: https://orcid.org/0000-0002-2330-9444)
- Wouter van Rheenen (ORCID: https://orcid.org/0000-0002-5860-1533)
- Renske I. Wadman (ORCID: https://orcid.org/0000-0003-0339-5506)
- Paul J. Hop (ORCID: https://orcid.org/0000-0002-9007-7436)
- Robin Geene
- Joris V Kortooms
- Joyce van der Sel
- Demi Gommers (ORCID: https://orcid.org/0009-0003-7411-1352)
- Ramona A. J. Zwamborn
- Jan H. Veldink
- Fay-Lynn Asselman
Institutions
- Utrecht University (NL)
- Heidelberg University (DE)
- University Hospital Heidelberg (DE)
- University Medical Center Utrecht (NL)
Publication Details
- Journal
- iScience
- Published
- 2025-04-17
- DOI
- https://doi.org/10.1016/j.isci.2025.112461
- Citations
- 1
- Primary Topic
- Neurogenetic and Muscular Disorders Research
- Type
- article
- Field-Weighted Citation Impact
- 1.63
Funders
- Johns Hopkins University
- European Commission
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- Prinses Beatrix Spierfonds
- Stichting Spieren voor Spieren
- Horizon 2020 Framework Programme
- European Research Council
- H2020 European Research Council
- H2020 Marie Skłodowska-Curie Actions