Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene

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The recessive autosomal disorder known as ICF syndrome1,2,3 (for immunodeficiency, centromere instability and facial anomalies; Mendelian Inheritance in Man number 242860) is characterized by variable reductions in serum immunoglobulin levels which cause most ICF patients to succumb to infectious diseases before adulthood. Mild facial anomalies include hypertelorism, low-set ears, epicanthal folds and macroglossia. The cytogenetic abnormalities in lymphocytes are exuberant: juxtacentromeric heterochromatin is greatly elongated and thread-like in metaphase chromosomes, which is associated with the formation of complex multiradiate chromosomes. The same juxtacentromeric regions are subject to persistent interphase self-associations and are extruded into nuclear blebs or micronuclei. Abnormalities are largely confined to tracts of classical satellites 2 and 3 at juxtacentromeric regions of chromosomes 1, 9 and 16. Classical satellite DNA is normally heavily methylated at cytosine residues, but in ICF syndrome it is almost completely unmethylated in all tissues4. ICF syndrome is the only genetic disorder known to involve constitutive abnormalities of genomic methylation patterns. Here we show that five unrelated ICF patients have mutations in both alleles of the gene that encodes DNA methyltransferase 3B (refs 5, 6). Cytosine methylation is essential for the organization and stabilization of a specific type of heterochromatin, and this methylation appears to be carried out by an enzyme specialized for the purpose.

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Figure 1: Cytogenetic and methylation abnormalities in ICF syndrome.
Figure 2: Structure and expression of DNMT3B gene and protein.
Figure 3: Detection of mutations in DNMT3B in ICF patients.
Figure 4: The D809G mutation found in family R eliminates enzymatic activity of DNMT3B.


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We thank members of the European ICF Consortium for providing patient materials; B. F. Erlanger for discussions; E. Li for providing cDNA clone pMT3B for mouse Dnmt3B; B. Tycko for DNA samples; L. Nickelsen for technical assistance; K. Anderson for comments on the manuscript; and A. Niveleau for monoclonal antibody to m5C. Supported by grants from the NIH and the Leukemia Society of America (T.H.B.) and the Danish Research Councils and the Danish Cancer Society (N.T.).

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Correspondence to Timothy H. Bestor.

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