Mutations in Spliceosomal Genes PPIL1 and PRP17 Cause Neurodegenerative Pontocerebellar Hypoplasia with Microcephaly.
Amino Acid Sequence
Animals
Cell Cycle Proteins
/ chemistry
Cerebellar Diseases
/ complications
Cohort Studies
Female
Gene Knockout Techniques
/ methods
HEK293 Cells
Heredodegenerative Disorders, Nervous System
/ complications
Humans
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Microcephaly
/ complications
Mutation
/ genetics
Pedigree
Peptidylprolyl Isomerase
/ chemistry
Protein Structure, Secondary
Protein Structure, Tertiary
RNA Splicing Factors
/ chemistry
Spliceosomes
/ genetics
NMR
PCHM
PPIL1
PRP17
alternative splicing
brain development
cyclophilin
microcephaly
neurodegeneration
pontocerebellar hypoplasia
proline isomerase
recessive disease
spliceosome
Journal
Neuron
ISSN: 1097-4199
Titre abrégé: Neuron
Pays: United States
ID NLM: 8809320
Informations de publication
Date de publication:
20 01 2021
20 01 2021
Historique:
received:
21
11
2019
revised:
17
09
2020
accepted:
30
10
2020
pubmed:
22
11
2020
medline:
18
2
2021
entrez:
21
11
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33220177
pii: S0896-6273(20)30859-X
doi: 10.1016/j.neuron.2020.10.035
pmc: PMC8800389
mid: NIHMS1648052
pii:
doi:
Substances chimiques
CDC40 protein, human
0
Cell Cycle Proteins
0
RNA Splicing Factors
0
PPIL1 protein, human
EC 5.2.1.8
Peptidylprolyl Isomerase
EC 5.2.1.8
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
241-256.e9Subventions
Organisme : NHGRI NIH HHS
ID : UM1 HG008900
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS092772
Pays : United States
Organisme : NINDS NIH HHS
ID : F32 NS009800
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001442
Pays : United States
Organisme : Howard Hughes Medical Institute
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS048453
Pays : United States
Organisme : Wellcome Trust
ID : 094232
Pays : United Kingdom
Organisme : NIH HHS
ID : S10 OD026929
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS098004
Pays : United States
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : NINDS NIH HHS
ID : P30 NS047101
Pays : United States
Organisme : Medical Research Council
ID : MR/K011154/1
Pays : United Kingdom
Organisme : NHGRI NIH HHS
ID : U54 HG006504
Pays : United States
Organisme : Medical Research Council
ID : MR/M009084/1
Pays : United Kingdom
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests The authors declare no competing interests.
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