Mutations in Spliceosomal Genes PPIL1 and PRP17 Cause Neurodegenerative Pontocerebellar Hypoplasia with Microcephaly

Chai, Guoliang; Webb, Alice; Li, Chen; Antaki, Danny; Lee, Sang Moon; Breuss, Martin W.; Lang, Nhi; Stanley, Valentina; Anzenberg, Paula; Yang, Xiaoxu; Marshall, Trevor G; Gaffney, Patrick M.; Wierenga, Klaas J.; Chung, Brian Hon‐Yin; Tsang, Mandy Ho-Yin; Pais, Lynn; Lovgren, Alysia Kern; VanNoy, Grace E.; Rehm, Heidi L.; Mirzaa, Ghayda; Leon, Eyby; Diaz, Jullianne; Neumann, Alexander; Kalverda, Arnout P.; Manfield, Iain W.; Parry, David; Logan, Clare V.; Johnson, Colin A.; Bonthron, David T.; Valleley, Elizabeth M. A.; Issa, Mahmoud Y.; Abdel‐Ghafar, Sherif F.; Abdel‐Hamid, Mohamed S.; Jennings, Patricia A.; Zaki, Maha S.; Sheridan, Eamonn; Gleeson, Joseph G.

doi:10.1016/j.neuron.2020.10.035

Cited by 40 publications

(68 citation statements)

References 78 publications

(51 reference statements)

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“…is a member of the peptidyl-prolyl isomerase procyclin family and is frequently overexpressed in colon cancer cells (Chai et al, 2021). In summary, it is reasonable to speculate that the 7 SFs may play a role in the development of tumors, and the relationship between these SFs and lung cancer warrants further exploration in the future.…”

Section: Discussionmentioning

confidence: 95%

“…They drive the pathophysiology of lung cancer by promoting cell proliferation ( Su et al, 2012 ). Furthermore, the remaining SF PPIL1, which has not been directly reported in the literature to be associated with cancer, is a member of the peptidyl-prolyl isomerase procyclin family and is frequently overexpressed in colon cancer cells ( Chai et al, 2021 ). In summary, it is reasonable to speculate that the 7 SFs may play a role in the development of tumors, and the relationship between these SFs and lung cancer warrants further exploration in the future.…”

Section: Discussionmentioning

confidence: 99%

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Screening and Identification of Survival-Associated Splicing Factors in Lung Squamous Cell Carcinoma

et al. 2022

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Lung squamous cell carcinoma (LUSC) is a disease with high morbidity and mortality. Many studies have shown that aberrant alternative splicing (AS) can lead to tumorigenesis, and splicing factors (SFs) serve as an important function during AS. In this research, we propose an analysis method based on synergy to screen key factors that regulate the initiation and progression of LUSC. We first screened alternative splicing events (ASEs) associated with survival in LUSC patients by bivariate Cox regression analysis. Then an association network consisting of OS-ASEs, SFs, and their targeting relationship was constructed to identify key SFs. Finally, 10 key SFs were selected in terms of degree centrality. The validation on TCGA and cross-platform GEO datasets showed that some SFs were significantly differentially expressed in cancer and paracancer tissues, and some of them were associated with prognosis, indicating that our method is valid and accurate. It is expected that our method would be applied to a wide range of research fields and provide new insights in the future.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Screening and Identification of Survival-Associated Splicing Factors in Lung Squamous Cell Carcinoma

et al. 2022

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“…It is estimated that at least 20% of disease-causing mutations affect pre-mRNA splicing [80]. Spliceosomopathies are human diseases caused by mutations in the components of the major and minor spliceosomes, such as retinitis pigmentosa, myelodysplastic syndromes, spinal muscular atrophy, and craniofacial malformations [81][82][83]. Mutations in RNA-binding proteins involved in splicing regulation and disruptions in RNA metabolism, including mRNA splicing, have been associated with diseases, such as ASD [29], age-related disorders (frontotemporal lobar dementia [84], PD [85], and AD [21,86,87]).…”

Section: Ten Overlapping Dsgs In Neurological and Psychiatric Conditionsmentioning

confidence: 99%

Dysregulated Spliceosome Gene Expression May Be a Common Process in Brains of Neurological and Psychiatric Disorders

Chang-bin

Dai

et al. 2021

Preprint

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Alternative splicing (AS) contributes to the increased cellular and functional tissue complexity that is substantial in the brain. AS is tightly regulated because it is critical to many biological processes. Defective splicing is observed in several neurological and psychiatric disorders. While exonic mutations usually affect the splicing of an individual RNA, mutations in the splicing factors (components of spliceosome) frequently produce widespread disruption in the processing of many precursor-mRNAs. Thus, we tested the hypotheses that expression changes of spliceosome genes may be a common process and shared splicing pathways may be involved in complex polygenic brain disorders. We searched for expression changes of spliceosome-related genes (SGs) using a transcriptome database of several brain regions in 6 neurological and psychiatric disorders, namely Alzheimer’s disease, and autism spectrum, bipolar and major depressive disorder, Parkinson’s disease, and schizophrenia. Out of 255 SGs detected in brain, 138 showed excessive, significant changes in one or more of these disorders. Dysregulation of 10 SGs was shared in 4 disorders, and they were mostly downregulated. Six associated pathways were over-represented in all 6 disorders, including the major and the minor mRNA splicing pathways and RNA metabolism. Therefore, we found that aberrations in the mRNA splicing process may be a common trajectory to many complex brain disorders involving the spliceosome complex.

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“…In this issue of Neuron, Chai et al (2021) analyze several families with neurodegeneration and marked pontocerebellar hypoplasia and microcephaly and identify recessive (bi-allelic) mutations in peptidyl-prolyl isomerase-like 1 (PPIL1) and pre-RNA-processing-17 (PPR17). PPIL1 patient mutation knockin mice develop neuronal apoptosis.…”

mentioning

confidence: 99%

“…In this issue of Neuron, Chai and colleagues describe novel mutations in two genes leading to PCH with microcephaly (Chai et al, 2021). They culled this specific phenotype from a large cohort of >7,000 individuals with recessive congenital neurological disorders that they previously assembled.…”

mentioning

confidence: 99%

Splicing Control of Pontocerebellar Development

Paul

Scoles

Pulst

2021

Neuron

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Mutations in Spliceosomal Genes PPIL1 and PRP17 Cause Neurodegenerative Pontocerebellar Hypoplasia with Microcephaly

Cited by 40 publications

References 78 publications

Screening and Identification of Survival-Associated Splicing Factors in Lung Squamous Cell Carcinoma

Screening and Identification of Survival-Associated Splicing Factors in Lung Squamous Cell Carcinoma

Dysregulated Spliceosome Gene Expression May Be a Common Process in Brains of Neurological and Psychiatric Disorders

Splicing Control of Pontocerebellar Development

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