Screening of ENU mutagenized mice for ASD-like behavioral phenotypes (deficits in ultrasonic vocalizations (USVs) and nest-building behavior) in El Hayek et al., 2020 identified Kdm5a as a candidate gene; to validate this discovery, the authors generated a Kdm5a knockout mouse model (Kdm5a-/-) and demonstrated Kdm5a-/- mice not only exhibited disrupted ultrasonic vocalizations but also displayed repetitive behaviors, sociability deficits, cognitive dysfunction, and abnormal dendritic morphogenesis. Screening of whole exome sequencing and microarray data from a clinical cohort in this report also identified individuals with de novo heterozygous variants and homozygous variants in the KDM5A gene presenting with a phenotype characterized by autism spectrum disorder, developmental delay, intellectual disability, and delayed/absent speech development.
Molecular Function
This gene encodes a member of the Jumonji, AT-rich interactive domain 1 (JARID1) histone demethylase protein family. The encoded protein plays a role in gene regulation through the histone code by specifically demethylating lysine 4 of histone H3. The encoded protein interacts with many other proteins, including retinoblastoma protein, and is implicated in the transcriptional regulation of Hox genes and cytokines.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
KDM5A mutations identified in autism spectrum disorder using forward genetics
Model Type:
Genetic LOF
Model Genotype:
Homozygous
Mutation:
Kdm5a constitutive knockout mouse generated using crispr/cas9 to insert a single base pair (g-c) in exon 13, which results in a frameshift mutation in codon 581 to terminate translation after the inclusion of 8 aberrant amino acids.
Allele Type: Knockout
Strain of Origin: C57BL/6J
Genetic Background: C57BL/6J
ES Cell Line: NA
Mutant ES Cell Line: NA
Model Source: 33350388
