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

Nat Genet. 2000 Apr;24(4):368-71. doi: 10.1038/74191.


A goal of molecular genetics is to understand the relationship between basic nuclear processes, epigenetic changes and the numerous proteins that orchestrate these effects. One such protein, ATRX, contains a highly conserved plant homeodomain (PHD)-like domain, present in many chromatin-associated proteins, and a carboxy-terminal domain which identifies it as a member of the SNF2 family of helicase/ATPases. Mutations in ATRX give rise to characteristic developmental abnormalities including severe mental retardation, facial dysmorphism, urogenital abnormalities and alpha-thalassaemia. This 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 mitosis, suggesting that ATRX might exert other chromatin-mediated effects in the nucleus. Moreover, at metaphase, some ATRX is localized at or close to the ribosomal DNA (rDNA) arrays on the short arms of human acrocentric chromosomes. Here we show that mutations in ATRX give rise to changes in the pattern of methylation of several highly repeated sequences including the rDNA arrays, a Y-specific satellite and subtelomeric repeats. Our findings provide a potential link between the processes of chromatin remodelling, DNA methylation and gene expression in mammalian development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blotting, Southern
  • CpG Islands / genetics
  • DNA Helicases*
  • DNA Methylation*
  • DNA Mutational Analysis
  • DNA, Ribosomal / genetics
  • DNA, Ribosomal / metabolism
  • DNA, Satellite / genetics
  • DNA-Binding Proteins / genetics*
  • Down-Regulation / genetics
  • Fluorescent Antibody Technique, Indirect
  • Globins / biosynthesis
  • Globins / genetics
  • Humans
  • Intellectual Disability / genetics
  • Mutation*
  • Nuclear Proteins*
  • Repetitive Sequences, Nucleic Acid / genetics
  • Syndrome
  • Telomere / genetics
  • Transcription Factors / genetics*
  • X Chromosome / genetics
  • X-linked Nuclear Protein
  • alpha-Thalassemia / genetics


  • DNA, Ribosomal
  • DNA, Satellite
  • DNA-Binding Proteins
  • Nuclear Proteins
  • SMARCA2 protein, human
  • Transcription Factors
  • Globins
  • SMARCA4 protein, human
  • DNA Helicases
  • ATRX protein, human
  • X-linked Nuclear Protein