Human Molecular Genetics, 2001, Vol. 10, No. 10 1085-1092
© 2001 Oxford University Press
MECP2 truncating mutations cause histone H4 hyperacetylation in Rett syndrome
1Department of Genetics and 2Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA and 3Laboratory of Molecular Immunology, National Heart Lung and Blood Institute, NIH, Bethesda, MD, USA
Rett syndrome (RTT) is a mostly sporadic disorder of developmental regression, with loss of speech and purposeful hand use, microcephaly and seizures. It affects 1 in 10 000–15 000 females. RTT is caused by mutations in the MECP2 gene, which is located in Xq28 and subject to X inactivation. MECP2 encodes a methyl-CpG-binding protein that binds to 5-methyl-cytosine in DNA through its methyl-binding domain. Recruitment of a transcriptional silencing complex through MeCP2’s transcriptional repression domain results in histone deacetylation and chromatin condensation. To study the effects of two common truncating RTT mutations (R168X and 803delG), we examined mutant MeCP2 expression and global histone acetylation levels in clonal cell cultures from a female RTT patient with the mutant R168X allele on the active X chromosome, as well as in cells from a male hemizygous for the frameshift mutation 803delG (V288X). Both mutant alleles generated stable RNA transcripts, but no intact MeCP2 protein was detected with an antibody against the C-terminal region of MeCP2. Western blots with antibodies against acetylated histones H3 and H4 revealed that H4, but not H3, was hyperacetylated. By using antibodies against individual acetylated lysine residues, the observed H4 hyperacetylation was attributed to increased acetylation of lysine 16. Therefore, expression of endogenous truncating MECP2 alleles, in the absence of wild-type MeCP2 protein, is specifically associated with an increase in the mono-acetylated histone isoform H4K16. This observed effect may result in over-expression of MeCP2 target genes and, thus, play a role in the pathogenesis of RTT.
+ To whom correspondence should be addressed at: Department of Genetics, Stanford University School of Medicine, Stanford CA 94305-5323, USA; Tel: +1 650 725 8089; Fax: +1 650 725 8112; Email: francke@cmgm.stanford.edu
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