Portal de investigación
Monoallelic loss-of-function variants in GSK3B lead to autism and developmental delay
Autores de I3PT
Participantes ajenos a I3PT
- Tan, SW
- Zhang, QM
- Zhan, R
- Luo, S
- Han, YL
- Yu, B
- Muss, C
- Pingault, V
- Marlin, S
- Delahaye, A
- Peters, S
- Perne, C
- Kreiss, M
- Racine, C
- Tran-Mau-Them, F
- Phornphutkul, C
- Besterman, AD
- Martinez, J
- Wang, XX
- Tian, XY
- Srivastava, S
- Urion, DK
- Madden, JA
- Saif, HA
- Morrow, MM
- Begtrup, A
- Li, X
- Jurgensmeyer, S
- Leahy, P
- Zhou, SM
- Li, FX
- Hu, ZM
- Tan, JQ
- Xia, K
- Guo, H
Grupos de Investigación
Abstract
De novo variants adjacent to the canonical splicing sites or in the well-defined splicing-related regions are more likely to impair splicing but remain under-investigated in autism spectrum disorder (ASD). By analyzing large, recent ASD genome sequencing cohorts, we find a significant burden of de novo potential splicing-disrupting variants (PSDVs) in 5048 probands compared to 4090 unaffected siblings. We identified 55 genes with recurrent de novo PSDVs that were highly intolerant to variation. Forty-six of these genes have not been strongly implicated in ASD or other neurodevelopmental disorders previously, including GSK3B. Through international, multicenter collaborations, we assembled genotype and phenotype data for 15 individuals with GSK3B variants and identified common phenotypes including developmental delay, ASD, sleeping disturbance, and aggressive behavior. Using available single-cell transcriptomic data, we show that GSK3B is enriched in dorsal progenitors and intermediate forms of excitatory neurons in the developing brain. We showed that Gsk3b knockdown in mouse excitatory neurons interferes with dendrite arborization and spine maturation which could not be rescued by de novo missense variants identified from affected individuals. In summary, our findings suggest that PSDVs may play an important role in the genetic etiology of ASD and allow for the prioritization of new ASD candidate genes. Importantly, we show that genetic variation resulting in GSK3B loss-of-function can lead to a neurodevelopmental disorder with core features of ASD and developmental delay.
Datos de la publicación
- ISSN/ISSNe:
- 1359-4184, 1476-5578
- Tipo:
- Article
- Páginas:
- 1952-1965
- PubMed:
- 39472663
- Enlace a otro recurso:
- www.scopus.com
MOLECULAR PSYCHIATRY SPRINGERNATURE
Citas Recibidas en Web of Science: 2
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- No hay documentos
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Campos de Estudio
Financiación
Cita
Tan SW,Zhang QM,Zhan R,Luo S,Han YL,Yu B,Muss C,Pingault V,Marlin S,Delahaye A et al. Monoallelic loss-of-function variants in <i>GSK3B</i> lead to autism and developmental delay. Mol Psychiatry. 2024. 30. (5):p. 1952-1965. DOI: 10.1038/s41380-024-02806-z.
Tan SW,Zhang QM,Zhan R,Luo S,Han YL,Yu B,Muss C,Pingault V,Marlin S,Delahaye A,Peters S,Perne C,Kreiss M,Spataro N,Trujillo JP,Racine C,Tran F,Phornphutkul C,Besterman AD,Martinez J,Wang XX,Tian XY,Srivastava S,Urion DK,Madden JA,Saif HA,Morrow MM,Begtrup A,Li X,Jurgensmeyer S,Leahy P,Zhou SM,Li FX,Hu ZM,Tan JQ,Xia K,Guo H. Monoallelic loss-of-function variants in <i>GSK3B</i> lead to autism and developmental delay. Mol Psychiatry. 2024. 30. (5):p. 1952-1965. IF:10,100. (1).