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

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Publication Year:
2020
Authors:
Guoliang Chai, Alice Webb, Chen Li, Danny Antaki, Sangmoon Lee, Martin W Breuss, Nhi Lang, Valentina Stanley, Paula Anzenberg, Xiaoxu Yang, Trevor Marshall, Patrick Gaffney, Klaas J Wierenga, Brian Hon-Yin Chung, Mandy Ho-Yin Tsang, Lynn S Pais, Alysia Kern Lovgren, Grace E VanNoy, Heidi L Rehm, Ghayda Mirzaa, Eyby Leon, Jullianne Diaz, Alexander Neumann, Arnout P Kalverda, Iain W Manfield, David A Parry, Clare V Logan, Colin A Johnson, David T Bonthron, Elizabeth M A Valleley, Mahmoud Y Issa, Sherif F Abdel-Ghafar, Mohamed S Abdel-Hamid, Patricia Jennings, Maha S Zaki, Eamonn Sheridan, Joseph G Gleeson
PubMed ID:
33220177
Funding Grants:
Public Summary:
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.
Scientific 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.