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.

常染色体隐性遗传的小脑发育不全和共济失调构成了一组由几个基本细胞过程破坏引起的异质性脑疾病。在这里，我们确定了 10 个家庭表现出涉及脑桥小脑发育不全伴小头畸形 (PCHM) 的神经退行性疾病。患者在编码剪接体成分肽基脯氨酰异构酶 Like-1 (PPIL1) 或 Pre-RNA Processing-17 (PRP17) 的基因中存在双等位基因突变。任一基因的小鼠敲除在早期胚胎发生中都是致命的，而PPIL1患者突变敲入小鼠表现出神经元特异性细胞凋亡。任何一种蛋白质的缺失都会影响剪接完整性，主要影响短而高 GC 含量的内含子和与脑部疾病有关的基因。PPIL1 和 PRP17 形成活性异构酶-底物相互作用，但我们发现异构酶活性对功能并不重要。因此，我们将破坏的剪接完整性和“主要剪接体病变”确定为 PCHM 和神经变性的新机制，并揭示剪接体脯氨酸异构酶的非酶功能。