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

Guo-Liang Xu, Timothy H. Bestor (), Déborah Bourc'his, Chih-Lin Hsieh, Niels Tommerup, Merete Bugge, Maj Hulten, Xiaoyan Qu, James J. Russo and Evani Viegas-Péquignot
Additional contact information
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

Nature, 1999, vol. 402, issue 6758, 187-191

Abstract: 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.

Date: 1999
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DOI: 10.1038/46052

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