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

TitleMutations in Spliceosomal Genes PPIL1 and PRP17 Cause Neurodegenerative Pontocerebellar Hypoplasia with Microcephaly.
Publication TypeJournal Article
Year of Publication2021
AuthorsChai, G, Webb, A, Li, C, Antaki, D, Lee, S, Breuss, MW, Lang, N, Stanley, V, Anzenberg, P, Yang, X, Marshall, T, Gaffney, P, Wierenga, KJ, Chung, BHon-Yin, Tsang, MHo-Yin, Pais, LS, Lovgren, AKern, VanNoy, GE, Rehm, HL, Mirzaa, G, Leon, E, Diaz, J, Neumann, A, Kalverda, AP, Manfield, IW, Parry, DA, Logan, CV, Johnson, CA, Bonthron, DT, Valleley, EMA, Issa, MY, Abdel-Ghafar, SF, Abdel-Hamid, MS, Jennings, P, Zaki, MAHS, Sheridan, E, Gleeson, JG
Date Published2021 01 20
KeywordsAmino Acid Sequence, Animals, Cell Cycle Proteins, Cerebellar Diseases, Cohort Studies, Female, Gene Knockout Techniques, HEK293 Cells, Heredodegenerative Disorders, Nervous System, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microcephaly, Mutation, Pedigree, Peptidylprolyl Isomerase, Protein Structure, Secondary, Protein Structure, Tertiary, RNA Splicing Factors, Spliceosomes

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.

Alternate JournalNeuron
PubMed ID33220177
Grant ListU54 HG006504 / HG / NHGRI NIH HHS / United States
/ HH / Howard Hughes Medical Institute / United States
R01 NS048453 / NS / NINDS NIH HHS / United States
094232 / WT / Wellcome Trust / United Kingdom
UL1 TR001442 / TR / NCATS NIH HHS / United States
MR/K011154/1 / MR / Medical Research Council / United Kingdom
R01 NS098004 / NS / NINDS NIH HHS / United States
UM1 HG008900 / HG / NHGRI NIH HHS / United States
S10 OD026929 / OD / NIH HHS / United States
P30 NS047101 / NS / NINDS NIH HHS / United States