Center for Molecular Medicine Cologne

Gehring, Niels - C 07

Molecular mechanism of X-linked intellectual disability caused by mutations in the UPF3B gene


Approximately 1-2% of the global population is affected by intellectual disability (ID), representing a serious medical, social and economic problem. The clinical symptoms and aetiology of ID are highly heterogeneous, making diagnosis and treatment of the disease difficult. X-linked ID caused by UPF3B mutations is well-suited for more detailed investigation due to its clearly defined genetic cause. In this project, we will study the function of UPF3B to better understand the development of ID.

Normal brain development depends on the precise operation of molecular programs that lead to proliferation, migration, and maturation of neuronal and glial cells. Alterations in these programs and processes can impair the development of the brain and lead to intellectual disability. A varying proportion of intellectual disability cases (15% to 50%) is caused by genetic factors, such as mutations in certain genes.

Several mutations in the gene encoding UPF3B have been identified as the cause of syndromic and non-syndromic forms of X-linked intellectual disability in more than 10 families. The identified mutations include missense, frameshift and nonsense mutations presumably leading to a loss of UPF3B function. Some UPF3B patients show additional disease states, including schizophrenia, autism and attention deficit hyperactivity disorder. Thus, the UPF3B protein is crucial for normal brain development and functions by a yet unknown mechanism.

Here, we propose to dissect the mechanism of X-linked intellectual disability caused by UPF3B mutations. To gain insights into the molecular function of UPF3B, we will mutate UPF3B in cultured cells by CRISPR/Cas9 and analyse the molecular effects using different high-throughput analyses.

Our Aims

  1. to generate UPF3B-deficient human neuronal cells 
  2. to identify cellular mRNAs regulated by UPF3B
  3. to determine the impact of UPF3B on human brain development

Previous Work

We have generated UPF3B K.O. HEK 293 and HeLa cells using CRISPR/Cas9 to study the cellular function of UPF3B. Preliminary analyses showed that these UPF3B K.O. cells did not differ phenotypically from their parental cells. In order to detect possible changes in gene expression, we analysed one of the HEK293 UPF3B K.O. cell lines using RNA-Seq.

To our surprise, we hardly detected any changes in gene expression in the UPF3B cells. A possible explanation for this observation is that some genes regulated by UPF3B are not expressed in HEK293 cells, or that there are very few mRNAs that are regulated only by UPF3B. We will address these two possibilities in the proposed work program by using neural-like cells for the UPF3B K.O. and by extending the analysis to additional RNA-related high-throughput assays.

  • Gehring NH, Neu-Yilik G, Schell T, Hentze MW, Kulozik AE (2003) Y14 and hUpf3b form an NMD-activating complex. Mol Cell 11: 939-49
  • Kunz JB, Neu-Yilik G, Hentze MW, Kulozik AE, Gehring NH (2006) Functions of hUpf3a and hUpf3b in nonsense-mediated mRNA decay and translation. RNA 12: 1015-22
  • Boehm V, Haberman N, Ottens F, Ule J, Gehring NH (2014) 3' UTR length and messenger ribonucleoprotein composition determine endocleavage efficiencies at termination codons. Cell Rep 9: 555-68
  • Linder B, Fischer U, Gehring NH (2015) mRNA metabolism and neuronal disease. FEBS Lett 589: 1598-606
  • Gerbracht JV, Gehring NH (2018) The exon junction complex: structural insights into a faithful companion of mammalian mRNPs. Biochem Soc Trans 46: 153-161
  • Wallmeroth D, Lackmann JW, Kueckelmann S, Altmüller J, Dieterich C, Boehm V, Gehring NH (2022). Human UPF3A and UPF3B enable fault-tolerant activation of nonsense-mediated mRNA decay. EMBO J., e109191. doi: 10.15252/embj.2021109191. Online ahead of print. PMID: 35451084.
  • Boehm V, Kueckelmann S, Gerbracht JV, Kallabis S, Britto-Borges T, Altmuller J, Kruger M, Dieterich C, and Gehring NH (2021). SMG5-SMG7 authorize nonsense-mediated mRNA decay by enabling SMG6 endonucleolytic activity. Nat Commun12, 3965. doi:10.1038/s41467-021-24046-3.
                                                      • Erkelenz S, Stankovic D, Mundorf J, Bresser T, Claudius AK, Boehm V, Gehring NH, and Uhlirova M (2021). Ecd promotes U5 snRNP maturation and Prp8 stability. Nucleic Acids Res49, 1688-1707. doi:10.1093/nar/gkaa1274.
                                                      • Gehring NH, and Roignant JY (2021). Anything but Ordinary - Emerging Splicing Mechanisms in Eukaryotic Gene Regulation. Trends Genet37, 355-372. doi:10.1016/j.tig.2020.10.008.
                                                      • Wang Q, Boenigk S, Boehm V, Gehring NH, Altmueller J, Dieterich C. (2021) Single cell transcriptome sequencing on the Nanopore platform with ScNapBar. RNA. 2021 Apr 27;27(7):763-70. doi: 10.1261/rna.078154.120.
                                                      • Gerbracht JV, Boehm V, Britto-Borges T, Kallabis S, Wiederstein JL, Ciriello S, Aschemeier DU, Kruger M, Frese CK, Altmuller J, Dieterich C, and Gehring NH (2020). CASC3 promotes transcriptome-wide activation of nonsense-mediated decay by the exon junction complex. Nucleic acids research 48, 8626-44.
                                                      Prof. Dr. Niels Gehring CMMC Cologne
                                                      Prof. Dr. Niels Gehring

                                                      Institute for Genetics - Center of Molecular Biosciences

                                                      CMMC - PI - C 07

                                                      +49 221 470 3873

                                                      Institute for Genetics - Center of Molecular Biosciences

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                                                      50674 Cologne

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                                                      Publications - Niels Gehring

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