2. Academic Validation
  3. Mutations in Spliceosomal Genes PPIL1 and PRP17 Cause Neurodegenerative Pontocerebellar Hypoplasia with Microcephaly

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

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: e.sheridan@leeds.ac.uk.
  • 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: jogleeson@ucsd.edu.
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.

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