Molecular and cellular events linking variants in the histone demethylase KDM5C to the intellectual disability disorder Claes-Jensen syndrome

Abstract

The widespread availability of genetic testing for those with neurodevelopmental disorders has highlighted the importance of many genes necessary for the proper development and function of the nervous system. One gene found to be genetically altered in the X-linked intellectual disability disorder Claes-Jensen syndrome is KDM5C, which encodes a histone demethylase that regulates transcription by altering chromatin. While the genetic link between KDM5C and cognitive (dys)function is clear, how KDM5C functions to control transcriptional programs within neurons to impact their growth and activity remains the subject of ongoing research. Here, we review our current knowledge of Claes-Jensen syndrome and discuss important new data using model organisms that have revealed the importance of KDM5C in regulating aspects of neuronal development and function. Continued research into the molecular and cellular activities regulated by KDM5C is expected to provide critical etiological insights into Claes-Jensen syndrome and highlight potential targets for developing therapies to improve the quality of life of those affected.

Keywords: CJ-XLID; Claes-Jensen syndrome; KDM5C; KDM5C-RD; MRXSCJ; animal models of disease; autism spectrum disorders; histone demethylase; intellectual disability; neurodevelopmental disorders.

Fig. 1.

The KDM5C gene that is genetically altered in individuals with Claes-Jensen syndrome encodes a conserved protein. (A) Genetic variants observed in individuals with Claes-Jensen syndrome. Types of genetic change are indicated by colored circles, with missense in black, frameshift in green, splice site in yellow, and nonsense variants in gray. Details of each variant can be found in Table 1. (B) Phylogenetic relationship between the four paralogous KDM5 family proteins in humans and the single orthologs in flies and worms. Domains are shown by colored boxes. Animal images generated using Biorender.com.

Fig. 2.

Neuronal functions of KDM5C that could contribute to Claes-Jensen syndrome. KDM5C is a transcriptional regulator required for several distinct aspects of neuronal development and function based on studies in animal models (mice, flies, and worms). See text for details. Model created using Biorender.com.