Alt. symbols: ICF | ICF1 | M.HsaIIIB

Approved name: DNA methyltransferase 3 beta
Alt. names: DNA (cytosine-5-)-methyltransferase 3 beta

Location: 20q11.21: 32762385 - 32809359 (+)
Gene type: protein_coding, 21 transcripts.

Scores: LoFtool: 0.009920 | pLI: 0.99977460 | LOEUF: 0.375

HGNC: 2979

NCBI: 1789, RefSeq: NG_007290.1

Ensembl: ENSG00000088305.19

LRG_56 | Status: public

OMIM: 602900

Expression | ProteinAtlas

DNMT3B encodes a de novo DNA methyltransferase, which can methylate unmethylated and hemimethylated DNA with equal efficiencies (PMID: 12359337). It is thus required for genome-wide de novo methylation and the establishment of DNA methylation patterns during development. It has also been thought to play roles in gene silencing and act as a transcriptional co-repressor in association with specific factors independently of DNA methylation.

Biallelic LOF mutations in DNMT3B are associated with autosomal recessive Immunodeficiency-centromeric instability-facial anomalies (ICF) syndrome type 1 [OMIM: 242860], which also features hypomethylation of DNA of a small fraction of the genome. ICF is characterized by facial dysmorphisms, immunodeficiency, and pathognomonic multi-branched configurations of chromosomes 1, 9, and 16 in PHA-stimulated lymphocytes due to increased frequency of somatic recombination. Immunodeficiency in these pati ents can range from isolated humoral defects such as hypogammaglobulinemia or agammaglobulinemia to a less commonly described CID affecting T cells, NK cells and/or neutrophils in addition to B cells. ICF patients have been found to have reduced memory B cells with concomitant increases in immature cells and a potential retention of autoreactive clones, as well as inverted CD4/CD8 ratios and increased in vitro susceptibility to activation-induced apoptosis of both T and B cells (PMID: 11496256, 11869951, 14645008). Both quantitative and qualitative defects in T and NK cells are also being increasingly reported (PMID: 23486536, 2386052, 30511102, 31520839). Thus, the relative contributions of intrinsic B-cell defects and defects in other cell types to the CVID-like phenotypes of these patients remains to be determined. Jin et al. (2008) found evidence of gene expression changes and promoter hypomethylation at key developmental genes in ICF1 patient-derived lymphoblastoid cell lines (PMID: 18029387). These genes subsequently lost histone modifications characteristic of transcriptionally repressed chromatin and gained modifications characteristic of active chromatin, highlighting the interrelationships between DNA methylation and chromatin state for regulation of transcription. Of note, ICF1 patients do not show defective α-satellite methylation, unlike ICF2 patients (PMID: 15580563). In 2013, Weemaes et al. compared a large cohort of ICF1 and ICF2 patients and noted that humoral immunodeficiency was generally more pronounced in ICF1 patients, though both ICF1 and ICF2 patients showed T- and B-cell abnormalities (PMID: 23486536). Finally, definite or potential mutations in both DNMT3B and ZBTB24 have been detected in additional large CVID patient cohorts by WES (PMID: 27379089, 28916186, 31942606). [Load More]