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.
Guoliang Chai  1 ,  Alice Webb  2 ,  Chen Li  1 ,  Danny Antaki  1 ,  Sangmoon Lee  1 ,  Martin W Breuss  1 ,  Nhi Lang  1 ,  Valentina Stanley  1 ,  Paula Anzenberg  1 ,  Xiaoxu Yang  1 ,  Trevor Marshall  1 ,  Patrick Gaffney  3 ,  Klaas J Wierenga  4 ,  Brian Hon-Yin Chung  5 ,  Mandy Ho-Yin Tsang  5 ,  Lynn S Pais  6 ,  Alysia Kern Lovgren  6 ,  Grace E VanNoy  6 ,  Heidi L Rehm  6 ,  Ghayda Mirzaa  7 ,  Eyby Leon  8 ,  Jullianne Diaz  8 ,  Alexander Neumann  9 ,  Arnout P Kalverda  10 ,  Iain W Manfield  10 ,  David A Parry  2 ,  Clare V Logan  2 ,  Colin A Johnson  2 ,  David T Bonthron  2 ,  Elizabeth M A Valleley  2 ,  Mahmoud Y Issa  11 ,  Sherif F Abdel-Ghafar  12 ,  Mohamed S Abdel-Hamid  12 ,  Patricia Jennings  13 ,  Maha S Zaki  11 ,  Eamonn Sheridan  14 ,  Joseph G Gleeson  15
Affiliations
  • 1. 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.
  • 2. Division of Molecular Medicine, Leeds Institute of Medical Research, University of Leeds, Leeds LS9 7TF, UK.
  • 3. Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
  • 4. Department of Clinical Genomics, Mayo Clinic, Jacksonville, FL 32224, USA.
  • 5. Department of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, U Hong Kong, Hong Kong, SAR, China.
  • 6. Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • 7. Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA.
  • 8. Department of Genetics and Metabolism, Children's National Hospital, Washington, DC 20010, USA.
  • 9. Freie Universität Berlin, Institute of Chemistry and Biochemistry, Laboratory of RNA Biochemistry, 14195 Berlin, Germany.
  • 10. Astbury Centre for Structural Molecular Biology and Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK.
  • 11. Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo 12311, Egypt.
  • 12. Medical Molecular Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo 12311, Egypt.
  • 13. Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA.
  • 14. Division of Molecular Medicine, Leeds Institute of Medical Research, University of Leeds, Leeds LS9 7TF, UK. Electronic address: [email protected].
  • 15. 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. Electronic address: [email protected].
PMID: 33220177 DOI: 10.1016/j.neuron.2020.10.035
Abstract

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.