MATR3 pathogenic variants differentially impair its cryptic splicing repression function

Authors: KHAN, MASHIAT - University Of Toronto; CHEN, XIAO - University Of Toronto; DIAS, MICHELLE - Baylor College Of Medicine; SANTOS, JHUNE - University Of Toronto; KOUR, SUKHLEEN - University Of Pittsburgh Medical Center; YOU, JUSTIN - University Of Toronto; VAN BRUGGEN, REBEKAH - Hospital For Sick Children (SICKKIDS); YOUSSEF, MOHIELDIN - Hospital For Sick Children (SICKKIDS); WAN, YING-WOOI - Texas Children'S Hospital; LIU, ZHANDONG - Baylor College Of Medicine; ROSENFELD, JILL - Baylor College Of Medicine; TAN, QIUMIN - University Of Alberta; PANDEY, UDAI - University Of Pittsburgh; YALAMANCHILI, HARI - Children'S Nutrition Research Center (CNRC); PARK, JEEHYE - University Of Toronto

Submitted to: FEBS Letters
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/3/2024
Publication Date: 2/6/2024
Citation: Khan, M., Chen, X.X., Dias, M., Santos, J.R., Kour, S., You, J., Van Bruggen, R., Youssef, M.M., Wan, Y., Liu, Z., Rosenfeld, J.A., Tan, Q., Pandey, U.B., Yalamanchili, H.K., Park, J. 2024. MATR3 pathogenic variants differentially impair its cryptic splicing repression function. FEBS Letters. 598:415-436. https://doi.org/10.1002/1873-3468.14806.
DOI: https://doi.org/10.1002/1873-3468.14806

Interpretive Summary: Matrin-3 (MATR3) is a critical RNA-binding protein involved in gene regulation and has been associated with several neurodegenerative and neurodevelopmental diseases. This study examines how different pathogenic variants of MATR3 affect its function in repressing cryptic splicing, a process where non-functional sequences within genes are mistakenly included in the final mRNA transcript. The research underscores the complexity of MATR3's role in gene regulation and how specific mutations can lead to distinct pathological outcomes by disrupting its normal functions. Understanding the molecular mechanisms by which MATR3 variants impair cryptic splicing repression can have broader implications for pediatric health, including nutrition and obesity research. Identifying how these variants influence gene expression may help elucidate pathways involved in metabolic regulation and energy balance. Furthermore, insights into MATR3’s role could potentially inform strategies for managing pediatric diabetes by targeting specific splicing events that affect insulin sensitivity or glucose metabolism. Ultimately, this research could lead to novel therapeutic approaches for addressing obesity and related metabolic conditions.

Technical Abstract: Matrin-3 (MATR3) is an RNA-binding protein implicated in neurodegenerative and neurodevelopmental diseases. However, little is known regarding the role of MATR3 in cryptic splicing within the context of functional genes and how disease-associated variants impact this function. We show that loss of MATR3 leads to cryptic exon inclusion in many transcripts. We reveal that ALS-linked S85C pathogenic variant reduces MATR3 solubility but does not impair RNA binding. In parallel, we report a novel neurodevelopmental disease-associated M548T variant, located in the RRM2 domain, which reduces protein solubility and impairs RNA binding and cryptic splicing repression functions of MATR3. Altogether, our research identifies cryptic events within functional genes and demonstrates how disease-associated variants impact MATR3 cryptic splicing repression function.