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

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

doi:10.1371/journal.pgen.1008460

Cited by 20 publications

(19 citation statements)

References 70 publications

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“…SNRPE is a component of spliceosomes that regulates pre-mRNA splicing through the formation of U snRNA assembly [18]. Our functional assay showed that SNRPE had a strong growth-promotive function in all cancer cell lines (HCT116, SW480, SUIT2, PANC1, OE33 and KYSE70 cells), but not in non-cancerous cells (HCEC-1CT, HPPEC and Het1A), suggesting that SNRPE is a strong candidate as a therapeutic target for tumor therapy.…”

Section: Discussionmentioning

confidence: 83%

The Identification of RNA-Binding Proteins Functionally Associated with Tumor Progression in Gastrointestinal Cancer

Konishi

Kashima

Goto

et al. 2021

Cancers

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Previous investigations have indicated that RNA-binding proteins (RBPs) are key molecules for the development of organs, differentiation, cell growth and apoptosis in cancer cells as well as normal cells. A bioinformatics analysis based on the mRNA expression and a somatic mutational database revealed the association between aberrant expression/mutations of RBPs and cancer progression. However, this method failed to detect functional alterations in RBPs without changes in the expression, thus leading to false negatives. To identify major tumor-associated RBPs, we constructed an siRNA library based on the database of RBPs and assessed the influence on the growth of colorectal, pancreatic and esophageal cancer cells. A comprehensive analysis of siRNA functional screening findings using 1198 siRNAs targeting 416 RBPs identified 41 RBPs in which 50% inhibition of cell growth was observed in cancer cells. Among these RBPs, 12 showed no change in the mRNA expression and no growth suppression in non-cancerous cells when downregulated by specific siRNAs. We herein report for the first time cancer-promotive RBPs identified by a novel functional assessment using an siRNA library of RBPs combined with expressional and mutational analyses.

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Section: Discussionmentioning

confidence: 83%

The Identification of RNA-Binding Proteins Functionally Associated with Tumor Progression in Gastrointestinal Cancer

Konishi

Kashima

Goto

et al. 2021

Cancers

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“…SNRPE is a member of a large family of polypeptides that are conserved in eukaryotes and archaebacteria ( 34 ). Previous studies have revealed that it is involved in RNA processing and mRNA degradation ( 35 , 36 ). Furthermore, a previous study has revealed that SNRPE is highly expressed in high-grade prostate cancer, promoting cell proliferation ( 37 ).…”

Section: Discussionmentioning

confidence: 99%

PSMC2, ORC5 and KRTDAP are specific biomarkers for HPV‑negative head and neck squamous cell carcinoma

Zeng

Rong

et al. 2021

Oncol Lett

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The prognosis of patients with human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) is poorer than those with HPV-positive HNSCC. The present study aimed to identify novel and specific biomarkers of HPV-negative HNSCC using bioinformatics analysis and associated experiments. The gene expression profiles of HPV-negative HNSCC tissues and corresponding clinical data were downloaded from The Cancer Genome Atlas database and used in a weighted gene co-expression network analysis. Genes in clinically significant co-expression modules were used to construct a protein-protein interaction (PPI) network. The genes demonstrating a high degree score in the PPI network and a high correlation with tumor grade were considered hub genes. The diagnostic value of the hub genes associated with HPV-negative and HPV-positive HNSCC was analyzed using differential expression gene (DEG) analysis, immunohistochemical (IHC) staining and a receiver operating characteristic (ROC) curve analysis. Seven genes [Serrate RNA effector molecule (SRRT), checkpoint kinase 2 (CHEK2), small nuclear ribonucleoprotein polypeptide E (SNRPE), proteasome 26S subunit ATPase 2 (PSMC2), origin recognition complex subunit 5 (ORC5), S100 calcium binding protein A7 and keratinocyte differentiation associated protein (KRTDAP)] were demonstrated to be hub genes in clinically significant co-expression modules. DEG, IHC and ROC curve analyses revealed that SRRT, CHEK2 and SNRPE were significantly upregulated in HPV-negative and HPV-positive HNSCC tissues compared with in adjacent tissues, and these genes demonstrated a high diagnostic value for distinguishing HNSCC tissues. However, PSMC2, ORC5 and KRTDAP were the only differentially expressed genes identified in HPV-negative HNSCC tissues, and these genes demonstrated a high diagnostic value for HPV-negative HNSCC. PSMC2, ORC5 and KRTDAP may therefore serve as novel and specific biomarkers for HPV-negative HNSCC, potentially improving the diagnosis and treatment of patients with HPV-negative HNSCC.

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“…Similarly, a patient with a mutation in TUBGCP5, which is a centrosomal component that affects microtubule nucleation and spindle orientation, presents with MCPH (146). Finally, a METTL5 variant has also recently been identified in a patient with clinical features matching that of MCPH, highlighting the role of epigenetics and transcriptional regulation in the etiology of MCPH (147). Although these three genes are not listed in OMIM as of August 2020 as MCPH genes, we expect that these will be included following database updates and identification of additional patients with mutations in these genes.…”

Section: Linking Cell Biology To Diseasementioning

confidence: 99%

Dissecting the Genetic and Etiological Causes of Primary Microcephaly

2020

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Autosomal recessive primary microcephaly (MCPH; "small head syndrome") is a rare, heterogeneous disease arising from the decreased production of neurons during brain development. As of August 2020, the Online Mendelian Inheritance in Man (OMIM) database lists 25 genes (involved in molecular processes such as centriole biogenesis, microtubule dynamics, spindle positioning, DNA repair, transcriptional regulation, Wnt signaling, and cell cycle checkpoints) that are implicated in causing MCPH. Many of these 25 genes were only discovered in the last 10 years following advances in exome and genome sequencing that have improved our ability to identify disease-causing variants. Despite these advances, many patients still lack a genetic diagnosis. This demonstrates a need to understand in greater detail the molecular mechanisms and genetics underlying MCPH. Here, we briefly review the molecular functions of each MCPH gene and how their loss disrupts the neurogenesis program, ultimately demonstrating that microcephaly arises from cell cycle dysregulation. We also explore the current issues in the genetic basis and clinical presentation of MCPH as additional avenues of improving gene/variant prioritization. Ultimately, we illustrate that the detailed exploration of the etiology and inheritance of MCPH improves the predictive power in identifying previously unknown MCPH candidates and diagnosing microcephalic patients.

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

Cited by 20 publications

References 70 publications

The Identification of RNA-Binding Proteins Functionally Associated with Tumor Progression in Gastrointestinal Cancer

The Identification of RNA-Binding Proteins Functionally Associated with Tumor Progression in Gastrointestinal Cancer

PSMC2, ORC5 and KRTDAP are specific biomarkers for HPV‑negative head and neck squamous cell carcinoma

Dissecting the Genetic and Etiological Causes of Primary Microcephaly

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