title: ICF, an immunodeficiency syndrome: DNA methyltransferase 3B involvement, chromosome anomalies, and gene dysregulation.
abstract: The immunodeficiency, centromeric region instability, and facial anomalies syndrome (ICF) is the only disease known to result from a mutated DNA methyltransferase gene, namely, DNMT3B. Characteristic of this recessive disease are decreases in serum immunoglobulins despite the presence of B cells and, in the juxtacentromeric heterochromatin of chromosomes 1 and 16, chromatin decondensation, distinctive rearrangements, and satellite DNA hypomethylation. Although DNMT3B is involved in specific associations with histone deacetylases, HP1, other DNMTs, chromatin remodelling proteins, condensin, and other nuclear proteins, it is probably the partial loss of catalytic activity that is responsible for the disease. In microarray experiments and real-time RT-PCR assays, we observed significant differences in RNA levels from ICF vs. control lymphoblasts for pro- and anti-apoptotic genes (BCL2L10, CASP1, and PTPN13); nitrous oxide, carbon monoxide, NF-kappaB, and TNFalpha signalling pathway genes (PRKCH, GUCY1A3, GUCY1B3, MAPK13; HMOX1, and MAP4K4); and transcription control genes (NR2F2 and SMARCA2). This gene dysregulation could contribute to the immunodeficiency and other symptoms of ICF and might result from the limited losses of DNA methylation although ICF-related promoter hypomethylation was not observed for six of the above examined genes. We propose that hypomethylation of satellite 2 at 1qh and 16qh might provoke this dysregulation gene expression by trans effects from altered sequestration of transcription factors, changes in nuclear architecture, or expression of noncoding RNAs.
authors.affiliation: Hayward Human Genetics Program, Tulane Medical School, New Orleans, LA 70112, USA. ehrlich@tulane.edu
authors.forename: Melanie
authors.initials: M
authors.lastname: Ehrlich
authors.forename: Cecilia
authors.initials: C
authors.lastname: Sanchez
authors.forename: Chunbo
authors.initials: C
authors.lastname: Shao
authors.forename: Rie
authors.initials: R
authors.lastname: Nishiyama
authors.forename: John
authors.initials: J
authors.lastname: Kehrl
authors.forename: Rork
authors.initials: R
authors.lastname: Kuick
authors.forename: Takeo
authors.initials: T
authors.lastname: Kubota
authors.forename: Samir M
authors.initials: SM
authors.lastname: Hanash
mesh_terms: D000818:Animals; D002869:Chromosome Aberrations; D018389:Codon, Nonsense; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000201:enzymology* / Q000235:genetics* / Q000276:immunology; D020411:Oligonucleotide Array Sequence Analysis; D000097584:DNA Methyltransferase 3B
chemical_list: D018389:Codon, Nonsense; D004248:DNA (Cytosine-5-)-Methyltransferases; D004273:DNA, Neoplasm; D000097584:DNA Methyltransferase 3B