Related Experiment Video

Updated: May 15, 2026

A Non-random Mouse Model for Pharmacological Reactivation of Mecp2 on the Inactive X Chromosome
08:27

A Non-random Mouse Model for Pharmacological Reactivation of Mecp2 on the Inactive X Chromosome

Published on: May 22, 2019

A regulatory path associated with X-linked intellectual disability and epilepsy links KDM5C to the polyalanine

Loredana Poeta1, Francesca Fusco, Denise Drongitis

  • 1Institute of Genetics and Biophysics Adriano Buzzati Traverso, Consiglio Nazionale delle Ricerche, Naples 80131, Italy.

American Journal of Human Genetics
|December 19, 2012
PubMed

Insights

Aristaless-related homeobox (ARX) gene mutations causing intellectual disability (ID) and epilepsy disrupt the regulation of KDM5C gene expression. This ARX-KDM5C pathway involves chromatin remodeling and impacts disease severity in children.

Area of Science:

  • Genetics
  • Neuroscience
  • Developmental Biology

Background:

  • Intellectual disability (ID) and epilepsy frequently co-occur, significantly impacting child development.
  • Mutations in the aristaless-related homeobox (ARX) gene, specifically polyalanine expansions, are linked to X-linked ID (XLID) and epilepsy syndromes.
  • Lysine-specific demethylase 5C (KDM5C) is implicated in XLID and chromatin remodeling.

Purpose of the Study:

  • To investigate the regulatory relationship between ARX and KDM5C in the context of XLID and epilepsy.
  • To determine how ARX polyalanine expansions affect KDM5C gene regulation and downstream effects.
  • To elucidate a potential ARX-dependent mechanism involving chromatin remodeling in ID and epilepsy.

Main Methods:

  • Analysis of ARX mutations with varying polyalanine expansions in individuals with XLID/epilepsy.
  • Assessment of ARX binding to the KDM5C regulatory region.
  • Quantitative RT-PCR to measure Kdm5c mRNA levels in murine Arx-knockout cells.
  • Evaluation of KDM5C protein levels and H3K4me3 signals during neuronal differentiation.

Main Results:

  • ARX directly regulates KDM5C expression via a conserved noncoding element.
  • Polyalanine expansions in ARX lead to hypomorphic mutations with reduced trans-activity and impaired KDM5C binding.
  • ARX mutations cause Kdm5c mRNA downregulation and decreased KDM5C protein in developing neurons.
  • Reduced KDM5C levels inversely correlate with increased H3K4me3, suggesting chromatin remodeling alterations.

Conclusions:

  • ARX polyalanine expansions disrupt KDM5C gene regulation.
  • The ARX-KDM5C interaction represents a potential pathway contributing to the pathophysiology of XLID and epilepsy.
  • Altered ARX function impacting KDM5C expression and chromatin remodeling may correlate with disease severity.

More Related Videos

A Novel Strategy Combining Array-CGH, Whole-exome Sequencing and In Utero Electroporation in Rodents to Identify Causative Genes for Brain Malformations08:22

A Novel Strategy Combining Array-CGH, Whole-exome Sequencing and In Utero Electroporation in Rodents to Identify Causative Genes for Brain Malformations

Published on: December 1, 2017

In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila06:41

In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila

Published on: August 20, 2019

Related Concept Videos

Sex-linked Disorders01:43

Sex-linked Disorders

Like autosomes, sex chromosomes contain a variety of genes necessary for normal body function. When a mutation in one of these genes results in biological deficits, the disorder is considered sex-linked.
Pleiotropy01:33

Pleiotropy

Pleiotropy is the phenomenon in which a single gene impacts multiple, seemingly unrelated phenotypic traits. For example, defects in the SOX10 gene cause Waardenburg Syndrome Type 4, or WS4, which can cause defects in pigmentation, hearing impairments, and an absence of intestinal contractions necessary for elimination. This diversity of phenotypes results from the expression pattern of SOX10 in early embryonic and fetal development. SOX10 is found in neural crest cells that form melanocytes,...
X-Inactivation01:58

X-Inactivation

The human X chromosome contains over ten times the number of genes as in the Y chromosome. Since males have only one X chromosome, and females have two, one might expect females to produce twice as many of the proteins, with undesirable results.
Exon Recombination02:32

Exon Recombination

The evolution of new genes is critical for speciation. Exon recombination, also known as exon shuffling or domain shuffling, is an important means of new gene formation. It is observed across vertebrates, invertebrates, and in some plants such as potatoes and sunflowers. During exon recombination, exons from the same or different genes recombine and produce new exon-intron combinations, which might evolve into new genes. 
Exon shuffling follows “splice frame rules.” Each exon has three reading...
Epigenetic Regulation01:46

Epigenetic Regulation

Epigenetic mechanisms play an essential role in healthy development. Conversely, precisely regulated epigenetic mechanisms are disrupted in diseases like cancer.
Epigenetic Regulation01:37

Epigenetic Regulation

Epigenetic changes alter the physical structure of the DNA without changing the genetic sequence and often regulate whether genes are turned on or off. This regulation ensures that each cell produces only proteins necessary for its function. For example, proteins that promote bone growth are not produced in muscle cells. Epigenetic mechanisms play an essential role in healthy development. Conversely, precisely regulated epigenetic mechanisms are disrupted in diseases like cancer.
X-chromosome...