MATR3 pathogenic variants differentially impair its cryptic splicing repression function.

Autor: Khan M; Department of Molecular Genetics, University of Toronto, Canada.; Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, Canada., Chen XXL; Department of Molecular Genetics, University of Toronto, Canada.; Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, Canada., Dias M; Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX, USA., Santos JR; Department of Molecular Genetics, University of Toronto, Canada.; Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, Canada., Kour S; Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, USA., You J; Department of Molecular Genetics, University of Toronto, Canada.; Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, Canada., van Bruggen R; Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, Canada., Youssef MMM; Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, Canada., Wan YW; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX, USA.; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Liu Z; Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX, USA., Rosenfeld JA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.; Baylor Genetics Laboratories, Houston, TX, USA., Tan Q; Department of Cell Biology, University of Alberta, Edmonton, Canada., Pandey UB; Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.; Department of Human Genetics, University of Pittsburgh, School of Public Health, Pittsburgh, PA, USA., Yalamanchili HK; Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX, USA.; USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA., Park J; Department of Molecular Genetics, University of Toronto, Canada.; Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, Canada.
Jazyk: angličtina
Zdroj: FEBS letters [FEBS Lett] 2024 Feb; Vol. 598 (4), pp. 415-436. Date of Electronic Publication: 2024 Feb 06.
DOI: 10.1002/1873-3468.14806
Abstrakt: 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.
(© 2024 The Authors. FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)
Databáze: MEDLINE
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