Mutations in Spliceosomal Genes PPIL1 and PRP17 Cause Neurodegenerative Pontocerebellar Hypoplasia with Microcephaly

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.

Keywords: NMR; PCHM; PPIL1; PRP17; alternative splicing; brain development; cyclophilin; microcephaly; neurodegeneration; pontocerebellar hypoplasia; proline isomerase; recessive disease; spliceosome.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cell Cycle Proteins / chemistry
  • Cell Cycle Proteins / genetics*
  • Cerebellar Diseases / complications
  • Cerebellar Diseases / diagnostic imaging
  • Cerebellar Diseases / genetics*
  • Cohort Studies
  • Female
  • Gene Knockout Techniques / methods
  • HEK293 Cells
  • Heredodegenerative Disorders, Nervous System / complications
  • Heredodegenerative Disorders, Nervous System / diagnostic imaging
  • Heredodegenerative Disorders, Nervous System / genetics
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microcephaly / complications
  • Microcephaly / diagnostic imaging
  • Microcephaly / genetics*
  • Mutation / genetics*
  • Pedigree
  • Peptidylprolyl Isomerase / chemistry
  • Peptidylprolyl Isomerase / genetics*
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • RNA Splicing Factors / chemistry
  • RNA Splicing Factors / genetics*
  • Spliceosomes / genetics*


  • CDC40 protein, human
  • Cell Cycle Proteins
  • RNA Splicing Factors
  • PPIL1 protein, human
  • Peptidylprolyl Isomerase

Supplementary concepts

  • Pontocerebellar Hypoplasia