Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA; Rady Children's Institute for Genomic Medicine, San Diego, CA 92130, USA.
Division of Molecular Medicine, Leeds Institute of Medical Research, University of Leeds, Leeds LS9 7TF, UK.
Neuron. 2021 Jan 20;109(2):241-256.e9. doi: 10.1016/j.neuron.2020.10.035. Epub 2020 Nov 20.
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.
常染色体隐性小脑发育不良伴共济失调是一组由多种基本细胞过程紊乱引起的异质性脑疾病。在这里，我们鉴定了 10 个家族，这些家族表现出一种涉及桥脑小脑发育不良伴小头畸形（PCHM）的神经退行性疾病。患者携带编码剪接体成分肽酰脯氨酰异构酶样 1（PPIL1）或前 RNA 加工 17（PRP17）的基因的双等位基因突变。这两种基因的小鼠敲除在胚胎早期都是致命的，而 PPIL1 患者突变敲入小鼠则表现出神经元特异性凋亡。两种蛋白质的缺失均影响剪接完整性，主要影响短和高 GC 含量内含子以及与脑疾病相关的基因。PPIL1 和 PRP17 形成一个活跃的异构酶-底物相互作用，但我们发现异构酶活性对于功能不是关键的。因此，我们确立了剪接完整性的破坏和“主要剪接体病”作为 PCHM 和神经退行性变的新机制，并揭示了剪接体脯氨酰异构酶的非酶功能。
