Abnormal methylation does not prevent X inactivation in ICF patients

DNA undermethylation is a characteristic feature of ICF syndrome and has be en implicated in the formation of the juxtacentromeric chromosomal abnormal ities of this rare syndrome. We have previously shown that in female ICF pa tients the inactive X chromosome (Xi) is also undermethylated. This result was unexpected since female ICF patients are not more severely affected tha n male patients. Here we show that CpG island methylation is abnormal in so me ICF patients but in other ICF patients, the difference in methylation pa ttern between Xi and Xa (active X) is maintained. The consequences of Xi un dermethylation on gene expression were investigated by enzyme assays. They showed that significant gene expression did not correlate with CpG island m ethylation status. The widespread Xi undermethylation does not affect overa ll Xi replication timing and does not prevent Barr body formation suggestin g that a normal methylation pattern is not required for normal chromatin or ganization of Xi. Molecular investigation of some X-chromosome intron regio ns showed that the methylation changes in ICF female patients extend to non CpG islands sequences. Our results suggest that the genetic alteration of DNA methylation in ICF syndrome has little consequence on X chromosome gene expression and chromatin organization.