A Regulatory Path Associated with X-Linked Intellectual Disability and Epilepsy Links KDM5C to the Polyalanine Expansions in ARX

Abstract

Intellectual disability (ID) and epilepsy often occur together and have a dramatic impact on the development and quality of life of the affected children. Polyalanine (polyA)-expansion-encoding mutations of aristaless-related homeobox (ARX) cause a spectrum of X-linked ID (XLID) diseases and chronic epilepsy, including infantile spasms. We show that lysine-specific demethylase 5C (KDM5C), a gene known to be mutated in XLID-affected children and involved in chromatin remodeling, is directly regulated by ARX through the binding in a conserved noncoding element. We have studied altered ARX carrying various polyA elongations in individuals with XLID and/or epilepsy. The changes in polyA repeats cause hypomorphic ARX alterations, which exhibit a decreased trans-activity and reduced, but not abolished, binding to the KDM5C regulatory region. The altered functioning of the mutants tested is likely to correlate with the severity of XLID and/or epilepsy. By quantitative RT-PCR, we observed a dramatic Kdm5c mRNA downregulation in murine Arx-knockout embryonic and neural stem cells. Such Kdm5c mRNA diminution led to a severe decrease in the KDM5C content during in vitro neuronal differentiation, which inversely correlated with an increase in H3K4me3 signal. We established that ARX polyA alterations damage the regulation of KDM5C expression, and we propose a potential ARX-dependent path acting via chromatin remodeling.

Disrupted Intricacy of Histone H3K4 Methylation in Neurodevelopmental Disorders

“…KDM5C is directly regulated by ARX , a homeobox gene frequently mutated in XLID and epilepsy [109]. A majority of the ARX variants cause a hypomorphic ARX allele, leading to a decrease in KDM5C expression, thus possibly altering the regulation of H3K4me.…”

The overdue promise of short tandem repeat variation for heritability

“…These mutations can result in phenotypic effects and lead to genetic disorders; several neurological diseases (spinocerebellar ataxias, Huntington’s disease, spinobulbar muscular atrophy, dentatorubral-pallidoluysian atrophy, intellectual disability, etc.) are a consequence of dramatically expanded STR alleles [7,40,41]. Many of these disease-associated STR expansions behave as dominant gain-of-function mutations [7].…”

Regulation of histone H3K4 methylation in brain development and disease

“…However, it has been reported that RNAinduced Kdm5c knockdown in rat cerebellar granule neurons reduces dendritic length, and furthermore, Kdm5c is essential for neuronal survival during zebrafish development [59]. Interestingly, in cultured Arx null mutant cells, Kdm5c levels are severely reduced in differentiating GABAergic neurons [61]. Furthermore, conditional Arx deletion in the ganglionic eminence which contributes the largest proportion of interneurons for the cerebral cortex, leads to seizure disorders and neurocognitive deficits in mice [83].…”

“…Furthermore, polyalanine ( polyA)-tract-expansion-encoding mutations in the aristaless-related homeobox transcriptional regulator (ARX, MIM no. 300382), considered to rank among the most frequent causes of XLMR and epilepsy, are thought to lead to a dramatic downregulation of the ARXdriven transcription of KDM5C and, as a secondary effect, excessive H3K4 trimethylation [61]. To summarize then, at least seven genes-MLL1, MLL2, MLL3, KDM5A, KDM5C, ARX, CUL4B-each ascribed an essential role in the regulation of H3K4 methylation, are linked to rare monogenic forms of neurodevelopmental disease, including intellectual disability and autism ( figure 1 and table 1).…”