Beyond Oncogenes: How Ras–MAPK Variants Influence
Neurodevelopment
P. Havlickova, A. Koutska, I. Kuta Smatanova, M. Fenckova
Faculty of Science, University of South Bohemia in Ceske
Budejovice, Branisovska 1760, Ceske Budejovice, 37005, Czech Republic
fenckm00@prf.jcu.cz
The
Ras–MAPK pathway, best known for its role in oncogenesis, is also critical for
brain development. Germline mutations in pathway components cause
RASopathies—the most common monogenic cause of intellectual disability (ID) and
autism spectrum disorder (ASD)—and large-scale sequencing studies continue to
uncover numerous additional variants in individuals with neurodevelopmental
disorders (NDDs). Most are missense substitutions with uncharacterized
functional effects, yet they often cluster within structural “hotspots” that
control nucleotide binding, GTP hydrolysis, dimerization, or autoinhibitory
regulation [1-3].
Here,
large-scale genomic datasets are combined with high-resolution structures of
Ras, B-Raf, MEK, and ERK to map these variants and infer their mechanistic
consequences. Structural patterns reveal recurrent modes of dysregulation and
show parallels with oncogenic mutations, indicating potential opportunities for
targeted drug repurposing.
This structural–functional perspective
refines pathogenicity assessment, explains phenotypic variability, and
identifies priorities for functional validation. By shifting from purely
statistical classification to mechanism-based interpretation, it establishes a
framework for developing mutation-specific therapeutic strategies in
Ras–MAPK–related neurodevelopmental disease.
2. Geoffray, M. M., Falissard, B., Green, J.,
Kerr, B., Evans, D. G., Huson, S., Burkitt-Wright, E., & Garg, S. (2021). Autism
Spectrum Disorder Symptom Profile Across the RASopathies. Frontiers in
psychiatry, 11, 585700. https://doi.org/10.3389/fpsyt.2020.585700
3. Wang, T., Kim, C. N., Bakken, T. E., Gillentine,
M. A., Henning, B., Mao, Y., Gilissen, C., SPARK Consortium, Nowakowski, T. J.,
& Eichler, E. E. (2022). Integrated gene analyses
of de novo variants from 46,612 trios with autism and developmental disorders.
Proceedings of the National Academy of Sciences of the United States of
America, 119(46), e2203491119. https://doi.org/10.1073/pnas.2203491119
This work is supported by by a grant
from the Czech Science Foundation (grant no. 23-07810S) and an EMBO
Installation grant (grant no. IG-5310-2023) to M. Fenckova.