期刊
NEURON
卷 109, 期 2, 页码 241-+出版社
CELL PRESS
DOI: 10.1016/j.neuron.2020.10.035
关键词
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资金
- Simons Foundation Autism Research Initiative (SFARI) [51486313]
- NIH [R01NS048453, R01NS09800]
- Qatar National Research Fund (QNRF) National Priorities Research Program (NPRP) [6-1463-3-351, UM1HG008900, U54HG006504, N01 268201700006I-0-26800029]
- Rady Children's Institute for Genomic Medicine
- UCSD Clinical and Translational Research Institute (CTRI) [UL1TR001442]
- UCSD Neuroscience Core [P30 NS047101]
- UCSD IGM Genomics Core [S10 OD026929]
- Egypt Science and Technology Development fund (STDF) [26040]
- University of Leeds
- Wellcome Trust [094232]
- MRC [MR/K011154/1] Funding Source: UKRI
A new mechanism involving disrupted splicing integrity and major spliceosome-opathies has been identified as a cause of PCHM and neurodegeneration, shedding light on the non-enzymatic function of a spliceosomal proline isomerase.
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.
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