A missense mutation in SNRPE linked to non-syndromal microcephaly interferes with U snRNP assembly and pre-mRNA splicing

Autoři: Tao Chen aff001;  Bin Zhang aff002;  Thomas Ziegenhals aff004;  Archana B. Prusty aff004;  Sebastian Fröhler aff001;  Clemens Grimm aff004;  Yuhui Hu aff002;  Bernhard Schaefke aff002;  Liang Fang aff002;  Min Zhang aff002;  Nadine Kraemer aff006;  Angela M. Kaindl aff006;  Utz Fischer aff004;  Wei Chen aff002
Působiště autorů: Laboratory for Functional Genomics and Systems Biology, Berlin Institute for Medical System Biology, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany aff001;  Department of Biology, Southern University of Science and Technology (SUSTech), Shenzhen, China aff002;  Cancer Science Institute of Singapore, National University of Singapore, Singapore aff003;  Department of Biochemistry, Theodor-Boveri-Institute, University of Würzburg, Würzburg, Germany aff004;  Academy for Advanced Interdisciplinary Studies, Southern University of Science and Technology (SUSTech), Shenzhen, China aff005;  Charité-Universitätsmedizin Berlin, Institute of Cell Biology and Neurobiology, Berlin, Germany aff006;  Charité-Universitätsmedizin Berlin, Department of Pediatric Neurology, Berlin, Germany aff007;  Charité-Universitätsmedizin Berlin, Center for Chronically Sick Children, Berlin, Germany aff008
Vyšlo v časopise: A missense mutation in SNRPE linked to non-syndromal microcephaly interferes with U snRNP assembly and pre-mRNA splicing. PLoS Genet 15(10): e32767. doi:10.1371/journal.pgen.1008460
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008460


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.

Klíčová slova:

Fibroblasts – Gene expression – Immunoprecipitation – Introns – Messenger RNA – RNA splicing – Zebrafish – Small nuclear RNA


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