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- Publisher Website: 10.1016/j.neuron.2020.10.035
- Scopus: eid_2-s2.0-85097224279
- PMID: 33220177
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Article: Mutations in Spliceosomal Genes PPIL1 and PRP17 Cause Neurodegenerative Pontocerebellar Hypoplasia with Microcephaly
Title | Mutations in Spliceosomal Genes PPIL1 and PRP17 Cause Neurodegenerative Pontocerebellar Hypoplasia with Microcephaly |
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Authors | Chai, GuoliangWebb, AliceLi, ChenAntaki, DannyLee, SangmoonBreuss, Martin W.Lang, NhiStanley, ValentinaAnzenberg, PaulaYang, XiaoxuMarshall, TrevorGaffney, PatrickWierenga, Klaas J.Chung, Brian Hon YinTsang, Mandy Ho YinPais, Lynn S.Lovgren, Alysia KernVanNoy, Grace E.Rehm, Heidi L.Mirzaa, GhaydaLeon, EybyDiaz, JullianneNeumann, AlexanderKalverda, Arnout P.Manfield, Iain W.Parry, David A.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, PatriciaZaki, Maha S.Sheridan, EamonnGleeson, Joseph G. |
Keywords | alternative splicing brain development cyclophilin microcephaly neurodegeneration NMR PCHM pontocerebellar hypoplasia PPIL1 proline isomerase PRP17 recessive disease spliceosome |
Issue Date | 20-Jan-2021 |
Publisher | Cell Press |
Citation | Neuron, 2021, v. 109, n. 2, p. 241-256.e9 How to Cite? |
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. |
Persistent Identifier | http://hdl.handle.net/10722/348832 |
ISSN | 2023 Impact Factor: 14.7 2023 SCImago Journal Rankings: 7.728 |
DC Field | Value | Language |
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dc.contributor.author | Chai, Guoliang | - |
dc.contributor.author | Webb, Alice | - |
dc.contributor.author | Li, Chen | - |
dc.contributor.author | Antaki, Danny | - |
dc.contributor.author | Lee, Sangmoon | - |
dc.contributor.author | Breuss, Martin W. | - |
dc.contributor.author | Lang, Nhi | - |
dc.contributor.author | Stanley, Valentina | - |
dc.contributor.author | Anzenberg, Paula | - |
dc.contributor.author | Yang, Xiaoxu | - |
dc.contributor.author | Marshall, Trevor | - |
dc.contributor.author | Gaffney, Patrick | - |
dc.contributor.author | Wierenga, Klaas J. | - |
dc.contributor.author | Chung, Brian Hon Yin | - |
dc.contributor.author | Tsang, Mandy Ho Yin | - |
dc.contributor.author | Pais, Lynn S. | - |
dc.contributor.author | Lovgren, Alysia Kern | - |
dc.contributor.author | VanNoy, Grace E. | - |
dc.contributor.author | Rehm, Heidi L. | - |
dc.contributor.author | Mirzaa, Ghayda | - |
dc.contributor.author | Leon, Eyby | - |
dc.contributor.author | Diaz, Jullianne | - |
dc.contributor.author | Neumann, Alexander | - |
dc.contributor.author | Kalverda, Arnout P. | - |
dc.contributor.author | Manfield, Iain W. | - |
dc.contributor.author | Parry, David A. | - |
dc.contributor.author | Logan, Clare V. | - |
dc.contributor.author | Johnson, Colin A. | - |
dc.contributor.author | Bonthron, David T. | - |
dc.contributor.author | Valleley, Elizabeth M.A. | - |
dc.contributor.author | Issa, Mahmoud Y. | - |
dc.contributor.author | Abdel-Ghafar, Sherif F. | - |
dc.contributor.author | Abdel-Hamid, Mohamed S. | - |
dc.contributor.author | Jennings, Patricia | - |
dc.contributor.author | Zaki, Maha S. | - |
dc.contributor.author | Sheridan, Eamonn | - |
dc.contributor.author | Gleeson, Joseph G. | - |
dc.date.accessioned | 2024-10-17T00:30:19Z | - |
dc.date.available | 2024-10-17T00:30:19Z | - |
dc.date.issued | 2021-01-20 | - |
dc.identifier.citation | Neuron, 2021, v. 109, n. 2, p. 241-256.e9 | - |
dc.identifier.issn | 0896-6273 | - |
dc.identifier.uri | http://hdl.handle.net/10722/348832 | - |
dc.description.abstract | <p>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 <em>PPIL1</em> 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.</p> | - |
dc.language | eng | - |
dc.publisher | Cell Press | - |
dc.relation.ispartof | Neuron | - |
dc.rights | This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. | - |
dc.subject | alternative splicing | - |
dc.subject | brain development | - |
dc.subject | cyclophilin | - |
dc.subject | microcephaly | - |
dc.subject | neurodegeneration | - |
dc.subject | NMR | - |
dc.subject | PCHM | - |
dc.subject | pontocerebellar hypoplasia | - |
dc.subject | PPIL1 | - |
dc.subject | proline isomerase | - |
dc.subject | PRP17 | - |
dc.subject | recessive disease | - |
dc.subject | spliceosome | - |
dc.title | Mutations in Spliceosomal Genes PPIL1 and PRP17 Cause Neurodegenerative Pontocerebellar Hypoplasia with Microcephaly | - |
dc.type | Article | - |
dc.identifier.doi | 10.1016/j.neuron.2020.10.035 | - |
dc.identifier.pmid | 33220177 | - |
dc.identifier.scopus | eid_2-s2.0-85097224279 | - |
dc.identifier.volume | 109 | - |
dc.identifier.issue | 2 | - |
dc.identifier.spage | 241 | - |
dc.identifier.epage | 256.e9 | - |
dc.identifier.eissn | 1097-4199 | - |
dc.identifier.issnl | 0896-6273 | - |