Letter | Published:

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

Abstract

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1

    Maraschio,P., Zuffardi,O., Dalla Fior,T. & Tieplo,L. Immunodeficiency, centromeric heterochromatin instability of chromosomes 1, 9, and 16, and facial anomalies; the ICF syndrome. J. Med. Genet. 25, 173–180 (1988).

  2. 2

    Hulten,M. Selective somatic pairing and fragility at 1q12 in a boy with common variable immunodeficiency. Clin. Genet. 14, 294 (1978).

  3. 3

    Tieplo,L. et al. Concurrent instability at specific sites of chromosomes 1, 9, and 16 resulting in multibranched chromosomes. Clin. Genet. 14, 313–314 (1978).

  4. 4

    Jeanpierre,M. et al. An embryonic-like methylation pattern of classical satellite DNA is observed in ICF syndrome. Hum. Mol. Genet. 2, 731–735 (1993).

  5. 5

    Okano,M., Xie,S. & Li,E. Cloning and characterization of a family of novel mammalian DNA (cytosine-5)-methyltransferases. Nature Genet. 19, 219–220 (1998).

  6. 6

    Robertson,K. D. et al. The human DNA methyltransferases (DNMTs) 1, 3a and 3b: coordinate mRNA expression in normal tissues and overexpression in tumors. Nucleic Acids Res. 27, 2291–2298 (1999).

  7. 7

    Sumner,A. T., Mitchell,A. R. & Ellis,P. M. A FISH study of chromosome fusion in the ICF syndrome: involvement of paracentric heterochromatin but not of the centromeres themselves. J. Med. Genet. 35, 833–835 (1998).

  8. 8

    Maraschio,P., Cortinovis,M., Dainotti,E., Tupler,R. & Tiepolo,L. Interphase cytogenetics of the ICF syndrome. Ann. Hum. Genet. 56, 273–288 (1992).

  9. 9

    Lubit,B. W., Pham,T. D., Miller,O. J. & Erlanger,B. F. Localization of 5-methylcytosine in human metaphase chromosomes by immunoelectron microscopy. Cell 9, 503–509 (1976).

  10. 10

    Yoder,J. A., Walsh,C. P. & Bestor,T. H. Cytosine methylation and the ecology of intragenomic parasites. Trends Genet. 13, 335–340 (1997).

  11. 11

    Miniou,P. et al. Abnormal methylation pattern in constitutive and facultative (X inactive chromosome) heterochromatin of ICF patients. Hum. Mol. Genet. 3, 2093–2102 (1994).

  12. 12

    Bourc'his,D. et al. Abnormal methylation does not prevent X inactivation in ICF patients. Cytogenet. Cell Genet. 84, 245–252 (1999).

  13. 13

    Wijmenga,C. et al. Localization of the ICF syndrome to chromosome 20 by homozygosity mapping. Am. J. Hum. Genet. 63, 803–809 (1998).

  14. 14

    Schuffenhauer,S. et al. DNA, FISH and complementation studies in ICF syndrome: DNA hypomethylation of repetitive and single copy loci and evidence for a trans acting factor. Hum. Genet. 96, 562–571 (1995).

  15. 15

    Schuler,G. D. Pieces of the puzzle: expressed sequence tags and the catalog of human genes. J. Mol. Med. 75, 694–698 (1997).

  16. 16

    Holliday,R. & Pugh,J. DNA modification mechanisms and gene activity during development. Science 187, 226–232 (1975).

  17. 17

    Posfai,J., Bhagwat,A. S., Posfai,G. & Roberts,R. J. Predictive motifs derived from cytosine methyltransferases. Nucleic Acids Res. 17, 2421–2435 (1989).

  18. 18

    Lauster,R., Trautner,T. A. & Noyer-Weidner,M. Cytosine-specific type II DNA methyltransferases. A conserved enzyme core with variable target-recognition domains. J. Mol. Biol. 206, 305–312 (1989).

  19. 19

    Klimasauskas,S., Kumar,S., Roberts,R. J. & Cheng,S. HhaI methyltransferase flips its target base out of the DNA helix. Cell 76, 357–369 (1994).

  20. 20

    Gibbons,R. J., Picketts,D. J., Villard,L. & Higgs,D. R. Mutations in a putative global transcriptional regulator cause X-linked mental retardation with athalassemia (ATR-X syndrome). Cell 80, 837–845 (1995).

  21. 21

    Stec,I. et al. WHSC1, a 90 kb SET domain-containing gene, expressed in early development and homologous to a Drosophila dysmorphy gene maps in the Wolf–Hirschorn syndrome critical region and is fused to IgH in t(4;14) multiple myeloma. Hum. Mol. Genet. 7, 1071–1082 (1998).

  22. 22

    Jeanpierre,M. Human satellites 2 and 3. Ann. Genet. 37, 163–171 (1994).

  23. 23

    Hsieh,C.-L. In vivo activity of murine de novo methyltransferases, Dnmt3a and Dnmt3b. Mol. Cell. Biol. (in the press).

  24. 24

    Jeddeloh,J. A., Stokes,T. L. & Richards,E. Maintenance of genomic methylation requires a SWI2/SNF2-like protein. Nature Genet. 22, 94–97 (1999).

  25. 25

    Brown,K. E. et al. Association of transcriptionally silent genes with Ikaros complexes at contromeric heterochromatin. Cell 91, 845–854 (1997).

  26. 26

    Chen,R. Z., Petterson,U., Beard,C., Jackson-Grusby,L. & Jaenisch,R. DNA hypomethylation leads to elevated mutation rates. Nature 395, 89–93 (1998).

  27. 27

    Bestor,T. H. The host defence function of genomic methylation patterns. Novartis Found. Symp. 214, 187–195 (1998).

  28. 28

    Hsieh,C.-L. Dependence of transcriptional repression on CpG methylation density. Mol. Cell. Biol. 14, 5487–5494 (1994).

  29. 29

    Reynaud,C. et al. Monitoring of urinary excretion of modified nucleosides in cancer patients using a set of six monoclonal antibodies. Cancer Lett. 61, 255–262 (1992).

Download references

Acknowledgements

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.).

Author information

Correspondence to Timothy H. Bestor.

Rights and permissions

Reprints and Permissions

About this article

Further reading

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.

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.