Children with Rett syndrome present autistic-like behaviour and specific clinical signs, such as hand wringing and loss of speech. Scientists previously showed that this X-linked neurodevelopmental disorder is caused by mutations in a gene on the X chromosome, which encodes methyl-CpG-binding protein-2 (MECP2).

As MECP2 regulates the transcriptional activity of other genes, a team led by Terumi Kohwi-Shigematsu of the Lawrence Berkeley National Laboratory, California, USA, searched for MECP2 target genes that might be dysregulated in mice with a defective MECP2 gene. Among them was DLX5, the expression of which almost doubled in MECP2-knockout mice.

The maternally expressed DLX5 gene showed loss of imprinting in lymphoblastoid cells from Rett-syndrome patients. The scientists found that, in mice, intact MECP2 was required for specifying repressive histone methylation in the region that contained the DLX5 gene, and for organizing a transcriptionally silent chromatin loop. In MECP2-null cells, such a loop was missing.

“The findings are an important piece in a very big puzzle”, according to Alan Percy of the University of Alabama, Birmingham, USA (ScienceNow, 21 December 2004).

In humans, DLX5 has an important role in the synthesis of γ-aminobutyric acid (GABA), which is a neurotransmitter that has been linked to other neurological disorders including epilepsy and Parkinson's disease. So the loss of imprinting might change the GABAergic neuron activity. “The next question is whether cranking up the DLX5 gene results in some of the problems of Rett syndrome”, says Kohwi-Shigematsu (ScienceNow, 21 December 2004).