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

Tao Chen; Bin Zhang; Thomas Ziegenhals; Archana B Prusty; Sebastian Fröhler; Clemens Grimm; Yuhui Hu; Bernhard Schaefke; Liang Fang; Min Zhang; Nadine Kraemer; Angela M Kaindl; Utz Fischer; Wei Chen

doi:10.1371/journal.pgen.1008460

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

PLoS Genet. 2019 Oct 31;15(10):e1008460. doi: 10.1371/journal.pgen.1008460. eCollection 2019 Oct.

Authors

Tao Chen¹, Bin Zhang^{2

3}, Thomas Ziegenhals⁴, Archana B Prusty⁴, Sebastian Fröhler¹, Clemens Grimm⁴, Yuhui Hu², Bernhard Schaefke^{2

5}, Liang Fang^{2

5}, Min Zhang², Nadine Kraemer^{6

7}, Angela M Kaindl^{6

7

8}, Utz Fischer⁴, Wei Chen^{2

5}

Affiliations

¹ Laboratory for Functional Genomics and Systems Biology, Berlin Institute for Medical System Biology, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
² Department of Biology, Southern University of Science and Technology (SUSTech), Shenzhen, China.
³ Cancer Science Institute of Singapore, National University of Singapore, Singapore.
⁴ Department of Biochemistry, Theodor-Boveri-Institute, University of Würzburg, Würzburg, Germany.
⁵ Academy for Advanced Interdisciplinary Studies, Southern University of Science and Technology (SUSTech), Shenzhen, China.
⁶ Charité-Universitätsmedizin Berlin, Institute of Cell Biology and Neurobiology, Berlin, Germany.
⁷ Charité-Universitätsmedizin Berlin, Department of Pediatric Neurology, Berlin, Germany.
⁸ Charité-Universitätsmedizin Berlin, Center for Chronically Sick Children, Berlin, Germany.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alternative Splicing*
Animals
Cell Line
Disease Models, Animal
Exome Sequencing
Female
HEK293 Cells
Homeodomain Proteins / genetics*
Humans
Intellectual Disability / genetics*
Microcephaly / genetics*
Mutation, Missense*
Pedigree
RNA Splicing
RNA, Messenger / genetics
Ribonucleoproteins, Small Nuclear / metabolism
Transcription Factors / genetics*
Zebrafish
snRNP Core Proteins / chemistry
snRNP Core Proteins / genetics*
snRNP Core Proteins / metabolism

Substances

Homeodomain Proteins
RNA, Messenger
Ribonucleoproteins, Small Nuclear
SNRPE protein, human
Transcription Factors
empty spiracles homeobox proteins
snRNP Core Proteins

Grants and funding

Tao Chen was funded by China Scholarship Council (CSC). This work was supported by Sino-German (NSFC-DFG) Cooperative Research Project (No. 31861133013), National Natural Science Foundation of China (No. 31771443), the Basic Research Grant from Science and Technology Innovation Commission of Shenzhen Municipal Government (No.KQTD20180411143432337 and No. JCYJ20170307105752508). The receiver of these three funds is Wei Chen. NSFC: http://www.nsfc.gov.cn/english/site_1/index.html CSC: https://www.chinesescholarshipcouncil.com Science and Technology Innovation Commission of Shenzhen Municipal Government: http://english.sz.gov.cn/govt/agencies/s/201811/t20181122_14604925.htm The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.