MATR3 Pathogenic Variants Differentially Impair Its Cryptic Splicing Repression Function

Authors

Mashiat Khan
Xiao Xiao Lily Chen
Michelle Dias
Jhune Rizsan Santos
Sukhleen Kour
Justin You
Rebekah van Bruggen
Mohieldin M M Youssef
Ying-Wooi Wan
Zhandong Liu
Jill A Rosenfeld
Qiumin Tan
Udai Bhan Pandey
Hari Krishna Yalamanchili
Jeehye Park

Language

English

Publication Date

2-1-2024

Journal

FEBS Letters

DOI

10.1002/1873-3468.14806

PMID

38320753

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.

Keywords

Humans, Amyotrophic Lateral Sclerosis, Exons, RNA-Binding Proteins, RNA, Nuclear Matrix-Associated Proteins, MATR3; RNA-Binding Protein; Amyotrophic Lateral Sclerosis; Cryptic Splicing; Neurodevelopmental Disease

Published Open-Access

yes

Recommended Citation

Khan, Mashiat; Chen, Xiao Xiao Lily; Dias, Michelle; et al., "MATR3 Pathogenic Variants Differentially Impair Its Cryptic Splicing Repression Function" (2024). Duncan NRI Faculty and Staff Publications. 161.
https://digitalcommons.library.tmc.edu/duncar_nri_pub/161