MATR3 pathogenic variants differentially impair its cryptic splicing repression function

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.

MATR3’s Role beyond the Nuclear Matrix: From Gene Regulation to Its Implications in Amyotrophic Lateral Sclerosis and Other Diseases

“…More strikingly, MATR3 depletion led to a decrease in the formation of DNA damage-induced RAD51 foci and negatively impacted DNA repair by HR [ 14 ]. MATR3 has also been shown to regulate the levels of RAD17 and UHRF2 [ 16 , 46 ], which have both been shown to have roles in DDR [ 47 , 48 , 49 , 50 ].…”

“…Many reports have shown that MATR3 interacts with a variety of proteins that are known to function in splicing regulation [ 15 , 33 , 46 , 61 ]. Several studies have shown that the major role of MATR3 is a repressor of exon inclusion [ 15 , 16 , 17 , 19 ]. MATR3’s splicing function is dependent on its RRM domains, while the ZnF domains are largely dispensable [ 15 ].…”

“…This function is mediated through the binding of MATR3 in the deep intronic regions where these cryptic sites are located. Another study recently examined global MATR3-dependent cryptic splicing events (CSEs) within functional genes [ 16 ]. Conforming to previous findings [ 15 ], the RRM domains, particularly RRM2, are required for mediating the CE repression function of MATR3 [ 16 ].…”

“…As MATR3 was initially described as a nuclear matrix protein, MATR3 may play a structural or scaffolding role. However, accumulating studies since its discovery have demonstrated its role in various molecular and cellular processes involving DNA and RNA, including chromatin organization [ 9 , 10 , 11 ], DNA transcription and repair [ 6 , 12 , 13 , 14 ], and RNA splicing [ 15 , 16 , 17 , 18 , 19 ] ( Figure 1 ). Recent studies have investigated its biological function in various cell types, including induced pluripotent stem cells, neuronal stem cells, differentiated neurons, and muscle cells, expanding our knowledge of the roles that MATR3 plays in modulating cellular health and function [ 10 , 11 , 12 , 20 , 21 , 22 , 23 ].…”

“…In addition, there have been an increasing number of studies implicating MATR3 in a variety of diseases. Most notably, missense mutations in MATR3 have been linked to amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease caused by the loss of motor neurons [ 24 ], as well as in neurodevelopmental diseases [ 16 , 25 ]. Furthermore, recent studies have revealed that MATR3 may play a critical role in other diseases, including cancer [ 26 , 27 , 28 , 29 , 30 , 31 ].…”