Abstract
Immunodeficiency, Centromeric Instability, Facial Anomalies (ICF) syndrome is a rare autosomal recessive disorder that is characterized by a marked immunodeficiency, severe hypomethylation of the classical satellites 2 and 3 associated with disruption of constitutive heterochromatin, and facial anomalies. Sixty percent of ICF patients have mutations in the DNMT3B (DNA methyltransferase 3B) gene, encoding a de novo DNA methyltransferase.In the present study, we have shown that, in ICF lymphoblasts and peripheral blood, juxtacentromeric heterochromatic genes undergo dramatic changes in DNA methylation, indicating that they are bona fide targets of the DNMT3B protein. DNA methylation in heterochromatic genes dropped from about 80% in normal cells to approximately 30% in ICF cells. Hypomethylation was observed in five ICF patients and was associated with activation of these silent genes. Although DNA hypomethylation occurred in all the analyzed heterochromatic genes and in all the ICF patients, gene expression was restricted to some genes, every patient having his own group of activated genes. Histone modifications were preserved in ICF patients. Heterochromatic genes were associated with histone modifications that are typical of inactive chromatin: they had low acetylation on H3 and H4 histones and were slightly enriched in H3K9Me3, both in ICF and controls. This was also the case for those heterochromatic genes that escaped silencing. This finding suggests that gene activation was not generalized to all the cells, but rather was restricted to a clonal cell population that may contribute to the phenotypic variability observed in ICF syndrome. A slight increase in H3K27 monomethylation was observed both in heterochromatin and active euchromatin in ICF patients; however, no correlation between this modification and activation of heterochromatic genes was found.
Highlights
ICF (Immunodeficiency, Centromeric Instability, and Facial Anomalies; OMIM #242860), is a rare autosomal recessive disorder
Patient ICF3 presented the cytogenetic rearrangements that are commonly associated with ICF syndrome; he did not suffer from immunodeficiency and had no facial anomalies
We have shown that juxtacentromeric heterochromatic genes lost DNA methylation and escaped silencing in ICF cells
Summary
ICF (Immunodeficiency, Centromeric Instability, and Facial Anomalies; OMIM #242860), is a rare autosomal recessive disorder. Most of the ICF patients were born from consanguineous marriages and about 60% had mutations in the DNMT3B (DNA methyltransferase 3B) gene that maps to the 20q11.2 region [1,2,3]. Several mutations have been described in ICF syndrome, most of them (79%) lying in the gene portion encoding the C-terminal catalytic domain. These mutations induce a decrease of the enzymatic activity. It has been postulated that there are two types of ICF patients: type 1 patients bearing mutations in the DNMT3B gene and type 2 patients without known mutations [4]. Mutations in the Dnmt3b gene negatively affect proper embryonic development [2,5]
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