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

Abstract

The recessive autosomal disorder known as ICF syndrome (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 tissues. 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.

Cancer cells express aberrant DNMT3B transcripts encoding truncated proteins

“…Supplementary Table 1 lists the properties of each aberrant transcript. We noted alternative splicing of several 5 0 exons, including exon 5 (Xu et al, 1999). The 5 0 half of each transcript could be amplified using a primer derived from exon 1A (data not shown), suggesting that the promoter originally identified for DNMT3B is used to generate the aberrant transcripts (Yanagisawa et al, 2002).…”

“…Dnmt1À/À embryonic stem cells display extensive demethylation of endogenous retroviral DNA (Li et al, 1992), and murine embryonic stem cells lacking Dnmt3b demonstrate hypomethylation of minor satellite sequences (Okano et al, 1999). Patients with a rare autosomal recessive syndrome, the immunodeficiency, centromere instability, facial anomalies (ICF) syndrome, have germline mutations in the DNMT3B gene (Hansen et al, 1999;Xu et al, 1999;Shirohzu et al, 2002), and lymphocytes from affected individuals display hypomethylation of repetitive DNA sequences. Furthermore, mice expressing Dnmt3b alleles similar to those found in ICF syndrome are small with abnormal craniofacial development and hypomethylation of repetitive elements, suggesting that these alleles encode hypomorphic proteins (Ueda et al, 2006).…”

Prognostic significance of DNA methyltransferase 3A mutations in cytogenetically normal acute myeloid leukemia: a study by the Acute Leukemia French Association

“…24,25,29 Interestingly, the somatic R882 mutations in DNMT3A found in AML are analogous to the inherited R823G mutation in DNMT3B, which was discovered in a human syndrome characterized by immunodeficiency, centrosome instability and facial abnormalities (ICF) in association with defects in genomic methylation. 48,49 In AML, the exact pathogenic mechanism by which DNMT3A mutations act is still enigmatic. Notably, Yan et al found that DNMT3A mutations enabled 32D cells, an interleukin-3-dependent mouse myeloid cell line, to acquire growth and survival advantage even without growth factor.…”

Epigenetic regulation of protein tyrosine phosphatases: potential molecular targets for cancer therapy

“…In fact, DNA hypomethylation, an early event in tumorigeneisis, can predispose cells to chromosomal rearrangements and destabiliztion of chromosomal organization. 17,68 In this context, it is noteworthy that methyl deficient diet can lead to both global DNA hypomethylation and localized or regional hypermethylation of genes such as tumor suppressor genes. 33,69 The most accepted concept is to envisage early changes in the hypomethylation of genes such as oncogenes followed by hypermethylation of genes such as tumor suppressor genes during cell transformation or in tumorigenesis, both processes resulting in gene deregulation.…”