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

Author

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  • Guo-Liang Xu

    (College of Physicians and Surgeons of Columbia University)

  • Timothy H. Bestor

    (College of Physicians and Surgeons of Columbia University)

  • Déborah Bourc'his

    (INSERM U383, Hôpital Necker-Enfants Malades)

  • Chih-Lin Hsieh

    (University of Southern California School of Medicine)

  • Niels Tommerup

    (Institute of Medical Biochemistry and Genetics, University of Copenhagen)

  • Merete Bugge

    (Institute of Medical Biochemistry and Genetics, University of Copenhagen)

  • Maj Hulten

    (University of Warwick)

  • Xiaoyan Qu

    (Columbia Genome Center, College of Physicians and Surgeons of Columbia University)

  • James J. Russo

    (Columbia Genome Center, College of Physicians and Surgeons of Columbia University)

  • Evani Viegas-Péquignot

    (INSERM U383, Hôpital Necker-Enfants Malades)

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.

Suggested Citation

  • Guo-Liang Xu & Timothy H. Bestor & Déborah Bourc'his & Chih-Lin Hsieh & Niels Tommerup & Merete Bugge & Maj Hulten & Xiaoyan Qu & James J. Russo & Evani Viegas-Péquignot, 1999. "Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene," Nature, Nature, vol. 402(6758), pages 187-191, November.
  • Handle: RePEc:nat:nature:v:402:y:1999:i:6758:d:10.1038_46052
    DOI: 10.1038/46052
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    Cited by:

    1. Linfeng Gao & Yiran Guo & Mahamaya Biswal & Jiuwei Lu & Jiekai Yin & Jian Fang & Xinyi Chen & Zengyu Shao & Mengjiang Huang & Yinsheng Wang & Gang Greg Wang & Jikui Song, 2022. "Structure of DNMT3B homo-oligomer reveals vulnerability to impairment by ICF mutations," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    2. Jiuwei Lu & Yiran Guo & Jiekai Yin & Jianbin Chen & Yinsheng Wang & Gang Greg Wang & Jikui Song, 2024. "Structure-guided functional suppression of AML-associated DNMT3A hotspot mutations," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    3. Romain O. Georges & Hugo Sepulveda & J. Carlos Angel & Eric Johnson & Susan Palomino & Roberta B. Nowak & Arshad Desai & Isaac F. López-Moyado & Anjana Rao, 2022. "Acute deletion of TET enzymes results in aneuploidy in mouse embryonic stem cells through decreased expression of Khdc3," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    4. Wande Li & Jing Zhou & Lijun Chen & Zhijun Luo & Yinzhi Zhao, 2011. "Lysyl Oxidase, A Critical Intra- and Extra-Cellular Target in the Lung for Cigarette Smoke Pathogenesis," IJERPH, MDPI, vol. 8(1), pages 1-24, January.
    5. Clara Cousu & Eléonore Mulot & Annie Smet & Sara Formichetti & Damiana Lecoeuche & Jianke Ren & Kathrin Muegge & Matthieu Boulard & Jean-Claude Weill & Claude-Agnès Reynaud & Sébastien Storck, 2023. "Germinal center output is sustained by HELLS-dependent DNA-methylation-maintenance in B cells," Nature Communications, Nature, vol. 14(1), pages 1-21, December.

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