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The EZH2 gene is a homolog of the Drosophila Polycomb group (PcG) gene enhancer of zest, a crucial regulator of homeotic gene expression. Several lines of evidence suggest a critical role for the EZH2 protein during normal and perturbed development of the haematopoietic and central nervous systems. Indeed, the EZH2 protein has been shown to associate with the Vav proto-oncoprotein and with the XNP protein, the product of a mental retardation gene. The EZH2 gene was previously reported to be located on chromosome 21q22 and was proposed as a candidate gene for some characteristics of the Down syndrome phenotype. We report here the genomic structure and fine mapping of the EZH2 gene. We demonstrate that the functional gene actually maps to chromosome 7q35 and that the sequence previously isolated from a chromosome 21 cosmid corresponds to a pseudogene. Finally, the nature of the EZH2 protein and its mapping to the critical region for malignant myeloid disorders lead us to propose the EZH2 gene is involved in the pathogenesis of 7q35-q36 aberrations in myeloid leukaemia.

Mutations in the XNP/ATR-X gene, located in Xq13.3, are associated with several X linked mental retardation syndromes, the best known being thalassaemia with mental retardation (ATR-X). The XNP/ATR-X protein belongs to the family of SWI/SNF DNA helicases and contains three C2-C2 type zinc fingers of unknown function. Previous studies have shown that 65% of mutations of XNP have been found within the zinc finger domain (encoded by exons 7, 8, and the beginning of exon 9) while 35% of the mutations have been found in the helicase domain extending over 3 kb at the C-terminus of the protein. Although diVerent types of mutations have been identified, no specific genotypephenotype correlation has been found, suggesting that gene alteration leads to a loss of function irrespective of mutation type. Our aims were to understand the function of the XNP/ATR-X protein better, with specific attention to the functional consequences of mutations to the zinc finger domain. We used monoclonal antibodies directed against the XNP/ ATR-X protein and performed immunocytochemical and western blot analyses, which showed altered or absent XNP/ ATR-X expression in cells of aVected patients. In addition, we used in vitro experiments to show that the zinc finger domain can mediate double stranded DNA binding and found that the DNA binding capacity of mutant forms in ATR-X patients is severely reduced. These data provide insights into the understanding of the functional significance of XNP/ ATR-X mutations. (J Med Genet 2000;37:746-751)

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