Please use this identifier to cite or link to this item:
https://doi.org/10.1371/journal.pgen.1008460
Title: | A missense mutation in SNRPE linked to non-syndromal microcephaly interferes with U snRNP assembly and pre-mRNA splicing | Authors: | Chen, T. Zhang, B. Ziegenhals, T. Prusty, A.B. Fröhler, S. Grimm, C. Hu, Y. Schaefke, B. Fang, L. Zhang, M. Kraemer, N. Kaindl, A.M. Fischer, U. Chen, W. |
Issue Date: | 2019 | Publisher: | Public Library of Science | Citation: | Chen, T., Zhang, B., Ziegenhals, T., Prusty, A.B., Fröhler, S., Grimm, C., Hu, Y., Schaefke, B., Fang, L., Zhang, M., Kraemer, N., Kaindl, A.M., Fischer, U., Chen, W. (2019). A missense mutation in SNRPE linked to non-syndromal microcephaly interferes with U snRNP assembly and pre-mRNA splicing. PLoS Genetics 15 (10) : e1008460. ScholarBank@NUS Repository. https://doi.org/10.1371/journal.pgen.1008460 | Rights: | Attribution 4.0 International | Abstract: | Malfunction of pre-mRNA processing factors are linked to several human diseases including cancer and neurodegeneration. Here we report the identification of a de novo heterozygous missense mutation in the SNRPE gene (c.65T>C (p.Phe22Ser)) in a patient with non-syndromal primary (congenital) microcephaly and intellectual disability. SNRPE encodes SmE, a basal component of pre-mRNA processing U snRNPs. We show that the microcephaly-linked SmE variant is unable to interact with the SMN complex and as a consequence fails to assemble into U snRNPs. This results in widespread mRNA splicing alterations in fibroblast cells derived from this patient. Similar alterations were observed in HEK293 cells upon SmE depletion that could be rescued by the expression of wild type but not mutant SmE. Importantly, the depletion of SmE in zebrafish causes aberrant mRNA splicing alterations and reduced brain size, reminiscent of the patient microcephaly phenotype. We identify the EMX2 mRNA, which encodes a protein required for proper brain development, as a major mis-spliced down stream target. Together, our study links defects in the SNRPE gene to microcephaly and suggests that alterations of cellular splicing of specific mRNAs such as EMX2 results in the neurological phenotype of the disease. © 2019 Chen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. | Source Title: | PLoS Genetics | URI: | https://scholarbank.nus.edu.sg/handle/10635/209639 | ISSN: | 1553-7390 | DOI: | 10.1371/journal.pgen.1008460 | Rights: | Attribution 4.0 International |
Appears in Collections: | Elements Staff Publications |
Show full item record
Files in This Item:
File | Description | Size | Format | Access Settings | Version | |
---|---|---|---|---|---|---|
10_1371_journal_pgen_1008460.pdf | 3.08 MB | Adobe PDF | OPEN | None | View/Download |
This item is licensed under a Creative Commons License