Impaired OTUD7A-dependent Ankyrin regulation mediates neuronal dysfunction in mouse and human models of the 15q13.3 microdeletion syndrome.
Journal
Molecular psychiatry
ISSN: 1476-5578
Titre abrégé: Mol Psychiatry
Pays: England
ID NLM: 9607835
Informations de publication
Date de publication:
04 2023
04 2023
Historique:
received:
07
01
2022
accepted:
19
12
2022
revised:
15
12
2022
medline:
26
5
2023
pubmed:
6
1
2023
entrez:
5
1
2023
Statut:
ppublish
Résumé
Copy number variations (CNVs) are associated with psychiatric and neurodevelopmental disorders (NDDs), and most, including the recurrent 15q13.3 microdeletion disorder, have unknown disease mechanisms. We used a heterozygous 15q13.3 microdeletion mouse model and patient iPSC-derived neurons to reveal developmental defects in neuronal maturation and network activity. To identify the underlying molecular dysfunction, we developed a neuron-specific proximity-labeling proteomics (BioID2) pipeline, combined with patient mutations, to target the 15q13.3 CNV genetic driver OTUD7A. OTUD7A is an emerging independent NDD risk gene with no known function in the brain, but has putative deubiquitinase function. The OTUD7A protein-protein interaction network included synaptic, axonal, and cytoskeletal proteins and was enriched for ASD and epilepsy risk genes (Ank3, Ank2, SPTAN1, SPTBN1). The interactions between OTUD7A and Ankyrin-G (Ank3) and Ankyrin-B (Ank2) were disrupted by an epilepsy-associated OTUD7A L233F variant. Further investigation of Ankyrin-G in mouse and human 15q13.3 microdeletion and OTUD7A
Identifiants
pubmed: 36604605
doi: 10.1038/s41380-022-01937-5
pii: 10.1038/s41380-022-01937-5
pmc: PMC10208958
mid: NIHMS1885169
doi:
Substances chimiques
Ankyrins
0
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
1747-1769Subventions
Organisme : NIMH NIH HHS
ID : R01 MH107182
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH097216
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2023. The Author(s).
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