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Abstract

Identifying Mechanism-Based and Mechanism-Agnostic Interventions for Gould Syndrome † †

by
Mao Mao
1,‡,
Cassandre Labelle-Dumais
1,‡,
Yoshihiro Ishikawa
1,
Matthew D. Lebedev
1 and
Douglas B. Gould
1,2,*
1
Department of Ophthalmology, University of California San Francisco, San Francisco, CA 94158, USA
2
Department of Anatomy, Institute for Human Genetics, Cardiovascular Research Institute, and Bakar Aging Research Institute, University of California San Francisco, San Francisco, CA 94158, USA
*
Author to whom correspondence should be addressed.
†
Presented at the 2nd COL4A1-A2 International Conference, Rome, Italy, 10 February 2025.
‡
These authors contributed equally to this work.
Proceedings 2025, 120(1), 10; https://doi.org/10.3390/proceedings2025120010
Published: 15 July 2025
Versions Notes

Gould syndrome is caused by mutations in the genes encoding collagen IV alpha 1 (COL4A1) and 2 (COL4A2)—fundamental basement membrane components that form collagen α1α1α2(IV) heterotrimers. The primary mechanism is a dominant interfering effect on collagen α1α1α2(IV) secretion, which is associated with elevated TGFβ signaling. We used preclinical mouse models to show that promoting collagen α1α1α2(IV) secretion or reducing TGFβ signaling ameliorates pathology, suggesting that these may represent mechanism-based interventions. Furthermore, we established a novel multifunctional murine Col4a1 allele to identify useful parameters for the development of mechanism-independent gene therapies.

Author Contributions

Conceptualization, M.M., C.L.-D., Y.I. and D.B.G.; methodology, M.M., C.L.-D. and Y.I.; validation, M.M., C.L.-D. and Y.I.; formal analysis, M.M., C.L.-D. and Y.I.; investigation, M.M., C.L.-D. and Y.I.; data curation, M.M., C.L.-D. and Y.I.; writing—original draft preparation, D.B.G.; writing—review and editing, M.M., C.L.-D., Y.I., M.D.L. and D.B.G.; supervision, D.B.G.; project administration, D.B.G.; funding acquisition, D.B.G. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the National Institutes of Health (NIH) under Award Numbers 1R21NS133610, 1RF1NS128217, R01EY019887, R01NS096173, R01NS110044, and R01NS083830 (D.B. Gould) from the National Institute of Neurological Diseases and Stroke and from All May See Foundation. The UCSF Department of Ophthalmology is supported by an NIH Core Grant from the National Eye Institute (P30 EY002162) and an unrestricted grant from Research to Prevent Blindness.

Institutional Review Board Statement

All experiments were approved by the Institutional Animal Care and Use Committee at the University of California, San Francisco, CA, USA (Protocols AN182181 and AN196112).

Informed Consent Statement

Not applicable.

Data Availability Statement

Data for this review are available in published manuscripts: DOI: 10.1016/j.matbio.2022.11.007; DOI: 10.1167/iovs.65.5.15; DOI: 10.1016/j.matbio.2022.05.001; DOI: 10.1083/jcb.202409153; DOI: 10.1242/dmm.034157.

Acknowledgments

We thank Yien-Ming Kuo for general research and administrative support. The authors have reviewed and edited the output and take full responsibility for the content of this publication.

Conflicts of Interest

The authors declare no conflicts of interest.
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Share and Cite

MDPI and ACS Style

Mao, M.; Labelle-Dumais, C.; Ishikawa, Y.; Lebedev, M.D.; Gould, D.B. Identifying Mechanism-Based and Mechanism-Agnostic Interventions for Gould Syndrome †. Proceedings 2025, 120, 10. https://doi.org/10.3390/proceedings2025120010

AMA Style

Mao M, Labelle-Dumais C, Ishikawa Y, Lebedev MD, Gould DB. Identifying Mechanism-Based and Mechanism-Agnostic Interventions for Gould Syndrome †. Proceedings. 2025; 120(1):10. https://doi.org/10.3390/proceedings2025120010

Chicago/Turabian Style

Mao, Mao, Cassandre Labelle-Dumais, Yoshihiro Ishikawa, Matthew D. Lebedev, and Douglas B. Gould. 2025. "Identifying Mechanism-Based and Mechanism-Agnostic Interventions for Gould Syndrome †" Proceedings 120, no. 1: 10. https://doi.org/10.3390/proceedings2025120010

APA Style

Mao, M., Labelle-Dumais, C., Ishikawa, Y., Lebedev, M. D., & Gould, D. B. (2025). Identifying Mechanism-Based and Mechanism-Agnostic Interventions for Gould Syndrome †. Proceedings, 120(1), 10. https://doi.org/10.3390/proceedings2025120010

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