Both de novo and recessive mutations have been identified in KDM5A-related neurodevelopmental conditions. The majority of variants are predicted to be loss-of-function. Missense variants have been identified and they result in reduced protein levels.
KDM5A encodes a histone lysine demethylase that removes methyl groups from lysine 4 of histone H3, resulting in repression of target genes. A constitutive knockout mouse model has demonstrated a critical role for KDM5A in brain development and function. Loss of KDM5A in the mouse results in disrupted ultrasonic vocalizations, increased repetitive behaviors, sociability deficits, cognitive dysfunction, and abnormal dendritic morphogenesis, in addition to impaired transcriptomes. Furthermore, it has been shown that KDM5A is required for establishing proper cellular identity in the hippocampus.
KDM5A