Further, ATRX is concentrated at pericentromeric heterochromatin in human and murine cells ( 9). The function of this protein is not yet known, but it is capable of interacting with two different heterochromatin proteins, mHP1α and EZH2 ( 7, 8).

ATRX encodes a putative ATP-dependent type II helicase of the SNF2 family which is widely expressed in development ( 5, 6). The initial reasons for believing that ATR-X syndrome might be a chromatin disease were primarily based on the observation that the ATRX protein had sequence similarity to known chromatin proteins. Mutations of this gene invariably give rise to mental retardation and can also result in facial and skeletal abnormalities, urogenital abnormalities, mild α-thalassemia and microcephaly. The α-thalassemia/mental retardation syndrome, X-linked (ATR-X syndrome OMIM 301040), Juberg–Marsidi syndrome (OMIM 309590), Sutherland–Haan syndrome (OMIM 309470) and Smith–Fineman–Myers syndrome (OMIM 309580) have all been shown to result from mutations in the ATRX gene ( 1– 4) located at Xq13. DISORDERS OF CHROMATIN-MEDIATED REPRESSION? ATR-X syndrome: a defect in the organization of repressive chromatin? Below we discuss examples where we think that these mechanisms of chromatin modification are aberrant. Conversely, the activation of gene expression can depend on the recruitment of chromatin complexes containing enzymes that can modify histones, for example via acetylation (histone acetyltransferases, HATs). Repression complexes are often recruited by the presence of DNA methylation and by the proteins that recognize methylated CpGs in mammalian DNA. Gene silencing has been correlated with the establishment of repressive chromatin structures and the presence of large complexes that include histone deacetylases (HDACs). The levels at which chromatin structure can be modified are complex. If so, what are the consequences for gene expression and human development, and does understanding these diseases as disorders of chromatin (‘chromatin diseases’) inform us either about chromatin-based mechanisms of gene expression themselves or about ways in which the disease phenotypes might be ameliorated? Therefore one would expect that there are genetic diseases in humans that result from mutations in the components of chromatin or in the enzymes that modify chromatin structure. It is now widely appreciated that, as well as simple transcription factor binding, the modification of DNA and chromatin is integral to the correct control of gene expression in mammals (Figures 1 and 2). Mutation of transcription factors also alters gene expression, and the phenotypic consequence of this will usually be felt by more than one target gene, and so tend to result in syndromes in which several different biological systems are disturbed. Altered expression of a single gene can result, for example, from deletion of that gene, from promoter mutations that alter its transcription, or from mutations that affect splicing or other levels of mRNA processing. Received JAccepted July 16, 2001.įailure of correct gene expression underlies many human genetic disorders.

Chromatin crossover definition genetics