PUBLICATION

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.
ID
ZDB-PUB-191102-24
Date
2019
Source
PLoS Genetics   15: e1008460 (Journal)
Registered Authors
Keywords
none
MeSH Terms
  • Alternative Splicing*
  • Animals
  • Cell Line
  • Disease Models, Animal
  • 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*
  • Whole Exome Sequencing
  • Zebrafish
  • snRNP Core Proteins/chemistry
  • snRNP Core Proteins/genetics*
  • snRNP Core Proteins/metabolism
PubMed
31671093 Full text @ PLoS Genet.
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.
Genes / Markers
Figures
Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes