Mutations in ATRX, encoding a SWI/SNF-like protein, cause diverse changes in the pattern of DNA methylation

A goal of molecular genetics is to understand the relationship between basi c nuclear processes, epigenetic changes and the numerous proteins that orch estrate these effects. One such protein, ATRX, contains a highly conserved plant homeodomain (PHD)-like domain, present in many chromatin-associated p roteins, and a carboxy-terminal domain which identifies it as a member of t he SNF2 family of helicase/ATPases(1,2). Mutations in ATRX give rise to cha racteristic developmental abnormalities including severe mental retardation , facial dysmorphism, urogenital abnormalities and alpha-thalassaemia(1). T his circumstantial evidence suggests that ATRX may act as a transcriptional regulator through an effect on chromatin. We have recently shown that ATRX is localized to pericentromeric heterochromatin during interphase and mito sis, suggesting that ATRX might exert other chromatin-mediated effects in t he nucleus. Moreover, at metaphase, some ATRX is localized at or close to t he ribosomal DNA (rDNA) arrays on the short arms of human acrocentric chrom osomes(3). Here we show that mutations in ATRX give rise to changes in the pattern of methylation of several highly repeated sequences including the r DNA arrays, a Y-specific satellite and subtelomeric repeats. Our findings p rovide a potential link between the processes of chromatin remodelling, DNA methylation and gene expression in mammalian development.