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.
摘要：
Matrin-3（MATR3）是一种与神经退行性疾病和神经发育疾病有关的RNA结合蛋白。然而,关于MATR3在功能基因背景下的隐秘剪接中的作用以及疾病相关变异如何影响该功能,人们知之甚少.我们表明，MATR3的丢失导致许多转录本中的隐性外显子包含。我们揭示了ALS连接的S85C致病变体降低了MATR3溶解度，但不损害RNA结合。并行,我们报道了一种新的神经发育疾病相关的M548T变体，位于RRM2域中，这会降低蛋白质的溶解度并损害MATR3的RNA结合和隐蔽剪接抑制功能。总之,我们的研究确定了功能基因内的隐性事件,并证明了疾病相关变异如何影响MATR3隐性剪接抑制功能.
