PUBLICATION
KLHL13 functional defects cause neurodevelopmental disorder in humans that can be rescued via inhibition of AURKB in cellular and animal models
- Authors
- Akhter, T., Ahmed, Z.M., Ji, Y., Schmidt, A., Azage, M., Palomares, M., Cremer, K., Engels, H., O Murphy, J., Peters, S., Mangold, E., Mlá, G.C., Taylor, R.J., Riazuddin, S., Riazuddin, S.
- ID
- ZDB-PUB-251030-3
- Date
- 2025
- Source
- Genetics in medicine : official journal of the American College of Medical Genetics : 101625101625 (Journal)
- Registered Authors
- Keywords
- AZD1152-HQPA, Intellectual disability, Kelch protein, genomic instability, macrocephaly
- MeSH Terms
-
- Animals
- Aurora Kinase B*/antagonists & inhibitors
- Aurora Kinase B*/genetics
- Aurora Kinase B*/metabolism
- Child
- Disease Models, Animal
- Exome Sequencing
- Female
- HEK293 Cells
- Humans
- Intellectual Disability/genetics
- Male
- Mutation, Missense
- Neurodevelopmental Disorders*/genetics
- Neurodevelopmental Disorders*/pathology
- Pedigree
- Zebrafish/genetics
- PubMed
- 41159445 Full text @ Genet. Med.
Citation
Akhter, T., Ahmed, Z.M., Ji, Y., Schmidt, A., Azage, M., Palomares, M., Cremer, K., Engels, H., O Murphy, J., Peters, S., Mangold, E., Mlá, G.C., Taylor, R.J., Riazuddin, S., Riazuddin, S. (2025) KLHL13 functional defects cause neurodevelopmental disorder in humans that can be rescued via inhibition of AURKB in cellular and animal models. Genetics in medicine : official journal of the American College of Medical Genetics. :101625101625.
Abstract
Purpose Neurodevelopmental disorders (NDDs) are characterized by limitations in brain development. This study aims to determine the genetic causes of NDD in humans.
Methods Exome sequencing was used to detect genetic variants in 4 families. In-silico protein modeling and overexpression in heterologous cells were used to determine the variants' impact. klhl13 loss of function was modeled in zebrafish, followed by rescue studies using human KLHL13 mRNA and an AURKB inhibitor.
Results We found one frameshift and three missense hemizygous variants of KLHL13 in individuals exhibiting NDD characteristics, such as intellectual disability and macrocephaly. 3D protein modeling simulation predicted the alteration of the KLHL13 protein folding for missense variants. Overexpression of NDD-associated variants in HEK293T cells revealed a significant impact on KLHL13-mediated cell cycle regulation during mitosis, leading to genomic instability. Knocking down klhl13 in zebrafish resulted in developmental deficits, which were rescued by co-injection of human KLHL13WT mRNA but not by transcripts encoding NDD variants. Treatment with AURKB selective inhibitor AZD1152-HQPA rescued genomic stability in heterologous cells and neurobehavioral deficits in zebrafish.
Conclusion Our results implicate KLHL13-mediated AURKB regulation as a significant contributor to NDD in humans. Inhibiting AURKB activity could serve as a potential therapy to improve brain development and cognitive function.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping