Mutations in spliceosomal genes PPIL1 and PRP17 cause neurodegenerative pontocerebellar hypoplasia with microcephaly

Autosomal-recessive cerebellar hypoplasia and ataxia comprise 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 impacted 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, however, we found 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.