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

Nature 402, 187-191 (11 November 1999) | doi:10.1038/46052; Received 10 August 1999; Accepted 13 October 1999

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

Guo-Liang Xu¹, Timothy H. Bestor¹, Déborah Bourc'his², Chih-Lin Hsieh³, Niels Tommerup⁴, Merete Bugge⁴, Maj Hulten⁵, Xiaoyan Qu⁶, James J. Russo⁶ and Evani Viegas-Péquignot²

Department of Genetics and Development, College of Physicians and Surgeons of Columbia University, New York 10032, USA
INSERM U383, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, 75743 Paris Cedex 15, France
Department of Urology, and Department of Biochemistry and Molecular Biology, University of Southern California School of Medicine, 1441 Eastlake Avenue, Los Angeles, California 90033, USA
Department of Medical Genetics, Institute of Medical Biochemistry and Genetics, University of Copenhagen, Glostrup DK-2600, Denmark
Department of Biological Sciences, University of Warwick, Coventry CV4 7AL, United Kingdom
Columbia Genome Center, College of Physicians and Surgeons of Columbia University, New York 10032, USA

Correspondence to: Timothy H. Bestor¹ Correspondence and requests for materials should be addressed to T.H.B. (e-mail: Email: THB12@columbia.edu).

The recessive autosomal disorder known as ICF syndrome^1,^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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