ATRX encodes a putative chromatin remodeling protein which belongs to the SNF2 family. This group of proteins is defined by the presence of a characteristic ATPase/helicase domain. At the N-terminus, ATRX also has a cysteine-rich region related to plant homeodomains which is very similar to domains in the DNMT3 family of DNA methyltransferases and another protein called DNMT3-like. This region has been called the ADD domain (ATRX, DNMT3, DNMT3-like). Both the helicase and ADD regions of ATRX have been highly conserved throughout mammalian development.
The distribution of ATRX in the nucleus is consistent with it being a heterochromatic protein. However, there are species- and cell-specific variations in its distribution during interphase between pericentromeric heterochromatin and nuclear bodies. In metaphase, ATRX remains associated with pericentromeric heterochromatin and is found on the short arms of human acrocentric chromosomes in the region of rDNA arrays. Although there is currently no biochemical evidence that ATRX is part of a well-defined multiprotein complex, there are several lines of evidence suggesting that it interacts with the heterochromatic protein HP1.
Mutations in the X-linked gene encoding ATRX cause severe developmental abnormalities resulting in mental retardation, urogenital abnormalities, and alpha thalassaemia, the last of which is due to down-regulation of alpha-globin gene expression. To date we have characterized over 100 individuals with ATRX syndrome. Twenty percent of mutations lie in the helicase domain and 60% in the ADD domain. All classes of ATRX mutation are associated with abnormalities in DNA methylation in heterochromatic regions. Hypomethylation is seen in the transcribed CpG-rich regions of the rDNA arrays and in subtelomeric sequences. Hypermethylation is seen in the Y-specific repeat DYZ2. Although subtle changes in DNA methylation have been observed in and around the alpha-globin cluster in erythroid precursors isolated from patients with ATRX syndrome, no consistent pattern has emerged that might explain the down-regulation of alpha-globin expression in these patients.
Although some cases of ATRX syndrome were originally thought to have null mutations, it is now clear that to date none of the patients are truly null. Recently we generated a knockout of the mouse ATRX gene. This null mutation is lethal in early embryonic development, and methylation is perturbed in embryonic stem cells and differentiated embryoid bodies in which ATRX has been knocked out. Like other SWI/SNF proteins such as DDM1 and LSH, ATRX appears to provide another important link between chromatin-associated proteins and DNA methylation.