DNA hypomethylation and unusual chromosome instability in cell lines from ICF syndrome patients

The ICF syndrome (immunodeficiency, centromeric region instability, facial anomalies) is a unique DNA methylation deficiency disease diagnosed by an e xtraordinary collection of chromosomal anomalies specifically in the vicini ty of the centromeres of chromosomes 1 and 16 (Chr1 and Chr16) in mitogen-s timulated lymphocytes. These aberrations include decondensation of centrome re-adjacent (qh) heterochromatin, multiradial chromosomes with up to 12. ar ms, and whole-arm deletions. We demonstrate that lymphoblastoid cell lines from two ICF patients exhibit these Chr1 and Chr16 anomalies in 61 % of the cells and continuously generate 1 qh or 16qh breaks. No other consistent c hromosomal abnormality was seen except for various telomeric associations, which had not been previously noted in ICF cells. Surprisingly, multiradial s composed of arms of both Chr1 and Chr16 were favored over homologous asso ciations and cells containing multiradials with 3 or >4 arms almost always displayed losses or gains of Chr1 or Chr16 arms from the metaphase. Our res ults suggest that decondensation of 1qh and 16qh often leads to unresolved Holliday junctions, chromosome breakage, arm missegregation, and the format ion of multiradials that may yield more stable chromosomal abnormalities, s uch as translocations. These cell lines maintained the abnormal hypomethyla tion in 1qh and 16qh seen in ICF tissues. The ICF-specific hypomethylation occurs in only a small percentage of the genome, e.g., ICF brain DNA had 7 % less 5-methylcytosine than normal brain DNA. The ICF lymphoblastoid cell lines, therefore, retain not only the ICF-specific pattern of chromosome re arrangements, but also of targeted DNA hypomethylation. This hypomethylatio n of heterochromatic DNA sequences is seen in many cancers and may predispo se to chromosome rearrangements in cancer as well as in ICF. Copyright(C)20 00S.KargerAG,Basel.