ArticleNeuron2021
Mutations in Spliceosomal Genes PPIL1 and PRP17 Cause Neurodegenerative Pontocerebellar Hypoplasia with Microcephaly.
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Article in Neuron, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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34citing papers in PubMed
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34 citing papers in PubMed, 56 citations in OpenAlex.
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- PPIL1 promotes hepatocellular carcinoma progression and associates with poor prognosis.Naunyn-Schmiedeberg's archives of pharmacology · 2026Article
- Genetic Insights in Hindbrain Abnormalities Through Network Analysis Expose Key Biological Pathways in Hindbrain Development.Cerebellum (London, England) · 2025Article
- Obesity induced by a high-fat diet regulates the MYC‒PPIL1 network in the mediation of asthenozoospermia.Basic and clinical andrology · 2025Article
- Transcriptome-wide outlier approach identifies individuals with minor spliceopathies.American journal of human genetics · 2025Article
- CETN3 deficiency induces microcephaly by disrupting neural stem/progenitor cell fate through impaired centrosome assembly and RNA splicing.EMBO molecular medicine · 2025Article
- Mutations in the spliceosomal gene SNW1 cause neurodevelopment disorders with microcephaly.The Journal of clinical investigation · 2025Article
- Recurrent de novo variants in the spliceosomal factor CRNKL1 are associated with severe microcephaly and pontocerebellar hypoplasia with seizures.American journal of human genetics · 2025Article
- Biallelic null variants in PNPLA8 cause microcephaly by reducing the number of basal radial glia.Brain : a journal of neurology · 2024Article
- Considerations for reporting variants in novel candidate genes identified during clinical genomic testing.Genetics in medicine : official journal of the American College of Medical Genetics · 2024Article
- Translatome analysis in acute ischemic stroke: Astrocytes and microglia exhibit differences in poststroke alternative splicing of expressed transcripts.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2024Article
- Enhancing recognition and interpretation of functional phenotypic sequences through fine-tuning pre-trained genomic models.Journal of translational medicine · 2024Article
- Considerations for reporting variants in novel candidate genes identified during clinical genomic testing.bioRxiv : the preprint server for biology · 2024Article
- Massively parallel characterization of regulatory elements in the developing human cortex.Science (New York, N.Y.) · 2024Article
- Cerebellum Lecture: the Cerebellar Nuclei-Core of the Cerebellum.Cerebellum (London, England) · 2024Review
- TREX tetramer disruption alters RNA processing necessary for corticogenesis in THOC6 Intellectual Disability Syndrome.Nature communications · 2024Article
- Broadening the phenotype and genotype spectrum of novel mutations in pontocerebellar hypoplasia with a comprehensive molecular literature review.BMC medical genomics · 2024Article
- Increased Diagnostic Yield by Reanalysis of Whole Exome Sequencing Data in Mitochondrial Disease.Journal of neuromuscular diseases · 2024Article
- Integrative transcriptome-proteome approach reveals key hypoxia-related features involved in the neuroprotective effects of Yang Xue oral liquid on Alzheimer's and Parkinson's disease.Frontiers in pharmacology · 2024Article
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Authors and funding
37 authors at 9 institutions in 4 countries.
Guoliang ChaiDepartment of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA; Rady Children's Institute for Genomic Medicine, San Diego, CA 92130, USA.
Alice WebbDivision of Molecular Medicine, Leeds Institute of Medical Research, University of Leeds, Leeds LS9 7TF, UK.
Chen LiDepartment of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA; Rady Children's Institute for Genomic Medicine, San Diego, CA 92130, USA.
Danny AntakiDepartment of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA; Rady Children's Institute for Genomic Medicine, San Diego, CA 92130, USA.
Sangmoon LeeDepartment of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA; Rady Children's Institute for Genomic Medicine, San Diego, CA 92130, USA.
Martin W BreussDepartment of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA; Rady Children's Institute for Genomic Medicine, San Diego, CA 92130, USA.
Nhi LangDepartment of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA; Rady Children's Institute for Genomic Medicine, San Diego, CA 92130, USA.
Valentina StanleyDepartment of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA; Rady Children's Institute for Genomic Medicine, San Diego, CA 92130, USA.
Paula AnzenbergDepartment of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA; Rady Children's Institute for Genomic Medicine, San Diego, CA 92130, USA.
Xiaoxu YangDepartment of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA; Rady Children's Institute for Genomic Medicine, San Diego, CA 92130, USA.
Trevor MarshallDepartment of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA; Rady Children's Institute for Genomic Medicine, San Diego, CA 92130, USA.
Patrick GaffneyGenes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
Klaas J WierengaDepartment of Clinical Genomics, Mayo Clinic, Jacksonville, FL 32224, USA.
Brian Hon-Yin ChungDepartment of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, U Hong Kong, Hong Kong, SAR, China.
Mandy Ho-Yin TsangDepartment of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, U Hong Kong, Hong Kong, SAR, China.
Lynn S PaisBroad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Alysia Kern LovgrenBroad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Grace E VanNoyBroad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Heidi L RehmBroad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Ghayda MirzaaCenter for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA.
Eyby LeonDepartment of Genetics and Metabolism, Children's National Hospital, Washington, DC 20010, USA.
Jullianne DiazDepartment of Genetics and Metabolism, Children's National Hospital, Washington, DC 20010, USA.
Alexander NeumannFreie Universität Berlin, Institute of Chemistry and Biochemistry, Laboratory of RNA Biochemistry, 14195 Berlin, Germany.
Arnout P KalverdaAstbury Centre for Structural Molecular Biology and Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK.
Iain W ManfieldAstbury Centre for Structural Molecular Biology and Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK.
David A ParryDivision of Molecular Medicine, Leeds Institute of Medical Research, University of Leeds, Leeds LS9 7TF, UK.
Clare V LoganDivision of Molecular Medicine, Leeds Institute of Medical Research, University of Leeds, Leeds LS9 7TF, UK.
Colin A JohnsonDivision of Molecular Medicine, Leeds Institute of Medical Research, University of Leeds, Leeds LS9 7TF, UK.
David T BonthronDivision of Molecular Medicine, Leeds Institute of Medical Research, University of Leeds, Leeds LS9 7TF, UK.
Elizabeth M A ValleleyDivision of Molecular Medicine, Leeds Institute of Medical Research, University of Leeds, Leeds LS9 7TF, UK.
Mahmoud Y IssaClinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo 12311, Egypt.
Sherif F Abdel-GhafarMedical Molecular Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo 12311, Egypt.
Mohamed S Abdel-HamidMedical Molecular Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo 12311, Egypt.
Patricia JenningsDepartment of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA.
Maha S ZakiClinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo 12311, Egypt.
Eamonn SheridanDivision of Molecular Medicine, Leeds Institute of Medical Research, University of Leeds, Leeds LS9 7TF, UK. Electronic address: e.sheridan@leeds.ac.uk.
Joseph G GleesonDepartment of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA; Rady Children's Institute for Genomic Medicine, San Diego, CA 92130, USA. Electronic address: jogleeson@ucsd.edu.
Children’s Institute · USUniversity of Leeds · GBBroad Institute · USNational Research Centre · EGChildren's National · USFreie Universität Berlin · DEMayo Clinic in Florida · USOklahoma Medical Research Foundation · USUniversity of California San Diego · US
Funding
UC San Diego Clinical and Translational Research InstituteUL1TR001442 · NCATS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI FIRESTEIN, GARY S, HOGARTH, MICHAEL · 2015 to 2024
$88.3MJoint Center for Mendelian GenomicsUM1HG008900 · NHGRI · BROAD INSTITUTE, INC. · PI O'DONNELL-LURIA, ANNE, REHM, HEIDI L · 2016 to 2020
$16.5MYale Center for Mendelian DisordersU54HG006504 · NHGRI · YALE UNIVERSITY · PI GERSTEIN, MARK BENDER, GUNEL, MURAT · 2012 to 2015
$11.0MU of Calif, San Diego Neuroscience Microscopy ImagingP30NS047101 · NINDS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI GLEESON, JOSEPH G, ZHENG, BINHAI · 2003 to 2022
$9.0MMolecular Characterization of Joubert SyndromeR01NS048453 · NINDS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI GLEESON, JOSEPH G · 2004 to 2020
$6.0MMolecular Characterization of Pontocerebellar HypoplasiaR01NS098004 · NINDS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI JOSEPH G GLEESON · 2016 to 2026
$4.6MMegalencephaly and segmental brain overgrowth in humansR01NS092772 · NINDS · SEATTLE CHILDREN'S HOSPITAL · PI MILLEN, KATHLEEN JOYCE · 2015 to 2019
$3.3MIllumina NovaSeq 6000 Sequencing SystemS10OD026929 · OD · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI JEPSEN, KRISTEN LYNN · 2019 to 2019
$600kMOLECULAR GENETICS OF INCONTINENTIA PIGMENTI TYPE 1F32NS009800 · NINDS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI MCDONALD, MARIE · 1994 to 1996
–Howard Hughes Medical InstituteMedical Research Council MR/K011154/1Medical Research Council MR/M009084/1NCATS NIH HHS UL1 TR001442NHGRI NIH HHS U54 HG006504NHGRI NIH HHS UM1 HG008900NIH HHS S10 OD026929NINDS NIH HHS F32 NS009800NINDS NIH HHS P30 NS047101NINDS NIH HHS R01 NS048453NINDS NIH HHS R01 NS092772NINDS NIH HHS R01 NS098004Wellcome TrustWellcome Trust 094232
Abstract
Autosomal-recessive cerebellar hypoplasia and ataxia constitute a group of heterogeneous brain disorders caused by disruption of several fundamental cellular processes. Here, we identified 10 families showing a neurodegenerative condition involving pontocerebellar hypoplasia with microcephaly (PCHM). Patients harbored biallelic mutations in genes encoding the spliceosome components Peptidyl-Prolyl Isomerase Like-1 (PPIL1) or Pre-RNA Processing-17 (PRP17). Mouse knockouts of either gene were lethal in early embryogenesis, whereas PPIL1 patient mutation knockin mice showed neuron-specific apoptosis. Loss of either protein affected splicing integrity, predominantly affecting short and high GC-content introns and genes involved in brain disorders. PPIL1 and PRP17 form an active isomerase-substrate interaction, but we found that isomerase activity is not critical for function. Thus, we establish disrupted splicing integrity and "major spliceosome-opathies" as a new mechanism underlying PCHM and neurodegeneration and uncover a non-enzymatic function of a spliceosomal proline isomerase.
Indexed as
Amino Acid SequenceAnimalsCell Cycle ProteinsCerebellar DiseasesCohort StudiesFemaleGene Knockout TechniquesHEK293 CellsHeredodegenerative Disorders, Nervous SystemHumansMaleMiceMice, Inbred C57BLMice, TransgenicMicrocephalyMutationCDC40 protein, humanCell Cycle ProteinsPeptidylprolyl IsomerasePPIL1 protein, humanRNA Splicing Factorsalternative splicingbrain developmentcyclophilinmicrocephalyneurodegenerationNMRPCHMpontocerebellar hypoplasiaPPIL1proline isomerasePRP17recessive diseasespliceosome
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