Three novel ZBTB24 mutations identified in Japanese and Cape Verdean type 2 ICF syndrome patients

J Hum Genet. 2013 Jul;58(7):455-60. doi: 10.1038/jhg.2013.56. Epub 2013 Jun 6.


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.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • Asian People / genetics*
  • Black People / genetics*
  • Cell Line
  • Centromere / metabolism
  • Child, Preschool
  • Chromosome Aberrations
  • Chromosomes, Human, Pair 1 / genetics
  • Chromosomes, Human, Pair 1 / metabolism
  • Chromosomes, Human, Pair 16 / genetics
  • Cloning, Molecular
  • DNA Methylation
  • Face / abnormalities*
  • Female
  • Genomics
  • Humans
  • Immunologic Deficiency Syndromes / diagnosis
  • Immunologic Deficiency Syndromes / genetics*
  • Male
  • Mice
  • Mutation
  • NIH 3T3 Cells
  • Primary Immunodeficiency Diseases
  • Recombinant Fusion Proteins / genetics
  • Repressor Proteins / genetics*
  • Sequence Analysis
  • Zinc Fingers / genetics


  • Recombinant Fusion Proteins
  • Repressor Proteins
  • ZBTB24 protein, human

Supplementary concepts

  • Immunodeficiency syndrome, variable