DNMT3B mutations and DNA methylation defect define two types of ICF syndrome

Abstract

ICF syndrome is a rare autosomal recessive disease characterized by variable immunodeficiency, centromeric instability, and facial abnormalities. Mutations in the catalytic domain of DNMT3B, a gene encoding a de novo DNA methyltransferase, have been recognized in a subset of patients. ICF syndrome is a genetic disease directly related to a genomic methylation defect that mainly affects classical satellites 2 and 3, both components of constitutive heterochromatin. The variable incidence of DNMT3B mutations and the differential methylation defect of alpha satellites allow the identification of two types of patients, both showing an undermethylation of classical satellite DNA. This classification illustrates the specificity of the methylation process and raises questions about the genetic heterogeneity of the ICF syndrome.

DNMT3A mutations in acute myeloid leukemia

“…The locations of mutations in DNMT3A are similar to those of DNMT3B mutations associated with the immunodeficiency, centromere instability, and facial anomalies (ICF) syndrome. 19,20 Recurrent mutations at a single amino acid position suggest a gain-of-function mechanism, although widely divergent mutations at many positions in a gene generally suggest loss of function, a pattern seen for many classic tumor-suppressor genes (e.g., TP53 and BRCA1). Indeed, several of the non-R882 mutations clearly cause loss of function in DNMT3A.…”

Vezf1 regulates genomic DNA methylation through its effects on expression of DNA methyltransferase Dnmt3b

“…Sixty percent to 90% of ICF patients have a missense mutation in the catalytic domain of DNMT3B, causing a partial loss of its activity (Hansen et al 1999;Xu et al 1999). There are, however, known ICF patients who lack DNMT3B mutations but have a distinctive set of DNA methylation defects, pointing to the existence of distinct ICF subtypes and the possible involvement of another gene (Jiang et al 2005). Alterations in DNA methylation are also seen in almost all cancers.…”

Hypomethylation at multiple maternally methylated imprinted regions including PLAGL1 and GNAS loci in Beckwith–Wiedemann syndrome

“…18 Methylation analysis of classical satellite DNA DNA methylation of classical satellites 2 and 3 was analysed by Southern blotting, as described. 19 Two micrograms of DNA were digested overnight with HpaII, MspI and McrBC, in separate tubes. Blots were hybridised with oligonucleotide probes specific for satellite 2 of chromosomes 1 and 16 and satellite 3 of chromosome 9.…”