title: Three novel ZBTB24 mutations identified in Japanese and Cape Verdean type 2 ICF syndrome patients.
abstract: Immunodeficiency, centromeric instability and facial anomalies (ICF) syndrome is a rare autosomal recessive disorder that shows DNA hypomethylation at pericentromeric satellite-2 and -3 repeats in chromosomes 1, 9 and 16. ICF syndrome is classified into two groups: type 1 (ICF1) patients have mutations in the DNMT3B gene and about half of type 2 (ICF2) patients have mutations in the ZBTB24 gene. Besides satellite-2 and -3 repeats, α-satellite repeats are also hypomethylated in ICF2. In this study, we report three novel ZBTB24 mutations in ICF2. A Japanese patient was homozygous for a missense mutation (C383Y), and a Cape Verdean patient was compound heterozygous for a nonsense mutation (K263X) and a frame-shift mutation (C327W fsX54). In addition, the second Japanese patient was homozygous for a previously reported nonsense mutation (R320X). The C383Y mutation abolished a C2H2 motif in one of the eight zinc-finger domains, and the other three mutations caused a complete or large loss of the zinc-finger domains. Our immunofluorescence analysis revealed that mouse Zbtb24 proteins possessing a mutation corresponding to either C383Y or R320X are mislocalized from pericentrometic heterochromatin, suggesting the importance of the zinc-finger domains in proper intranuclear localization of this protein. We further revealed that the proper localization of wild-type Zbtb24 protein does not require DNA methylation.
authors.affiliation: Division of Epigenomics and Development, Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Nitta
authors.forename: Motoko
authors.initials: M
authors.lastname: Unoki
authors.forename: Kenji
authors.initials: K
authors.lastname: Ichiyanagi
authors.forename: Tomoki
authors.initials: T
authors.lastname: Kosho
authors.forename: Tomonari
authors.initials: T
authors.lastname: Shigemura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takahashi
authors.forename: Guillaume
authors.initials: G
authors.lastname: Velasco
authors.forename: Claire
authors.initials: C
authors.lastname: Francastel
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.forename: Takeo
authors.initials: T
authors.lastname: Kubota
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sasaki
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D044466:Asian People / Q000235:genetics*; D044383:Black People / Q000235:genetics*; D002460:Cell Line; D002503:Centromere / Q000378:metabolism; D002675:Child, Preschool; D002869:Chromosome Aberrations; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics / Q000378:metabolism; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics; D003001:Cloning, Molecular; D019175:DNA Methylation; D005145:Face / Q000002:abnormalities*; D005260:Female; D023281:Genomics; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D051379:Mice; D009154:Mutation; D041681:NIH 3T3 Cells; D000081207:Primary Immunodeficiency Diseases; D011993:Recombinant Fusion Proteins / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics*; D017421:Sequence Analysis; D016335:Zinc Fingers / Q000235:genetics
chemical_list: D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; C560314:ZBTB24 protein, human