title: Three novel DNMT3B mutations in Japanese patients with ICF syndrome.
abstract: ICF syndrome is a rare autosomal recessive disorder characterized by immunodeficiency, centromeric instability, and facial anomalies. It is caused by mutations in a de novo DNA methyltransferase gene, DNMT3B. We here report the first three Japanese cases of ICF syndrome from two unrelated families. All patients had typical facial dysmorphism and immunoglobulin A (IgA) deficiency, but none of them had apparent mental retardation. Cytogenetic analysis of peripheral blood lymphocytes showed chromosomal abnormalities, including multiradial configurations and a stretching of the pericentromeric heterochromatin of chromosomes 1 and 16. Hypomethylation of classical satellite 2 DNA was also observed. Mutation analyses of DNMT3B revealed three novel mutations: patient 1 from the first family was a compound heterozygote for a nonsense mutation (Q42Term) and a missense mutation (R832Q); patients 2 and 3 from the second family were both homozygous for a missense mutation (S282P). The R832Q mutation occurred within the conserved methyltransferase domain, and thus may affect the enzyme activity directly. The S282P mutation, on the other hand, occurred close to the PWWP domain, which is presumably involved in protein-protein interaction. This is the first missense mutation mapped to the N-terminal half of the protein, suggesting that the region plays an important role in the regulation of the DNMT3B enzyme.
authors.affiliation: Division of Human Genetics, Department of Integrated Genetics, National Institute of Genetics, Mishima, Japan.
authors.forename: Hisao
authors.initials: H
authors.lastname: Shirohzu
authors.forename: Takeo
authors.initials: T
authors.lastname: Kubota
authors.forename: Azumi
authors.initials: A
authors.lastname: Kumazawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Sado
authors.forename: Takahito
authors.initials: T
authors.lastname: Chijiwa
authors.forename: Kouichi
authors.initials: K
authors.lastname: Inagaki
authors.forename: Isao
authors.initials: I
authors.lastname: Suetake
authors.forename: Shoji
authors.initials: S
authors.lastname: Tajima
authors.forename: Keiko
authors.initials: K
authors.lastname: Wakui
authors.forename: Yuko
authors.initials: Y
authors.lastname: Miki
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Hayashi
authors.forename: Yoshimitsu
authors.initials: Y
authors.lastname: Fukushima
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sasaki
mesh_terms: D000328:Adult; D001483:Base Sequence; D002675:Child, Preschool; D002869:Chromosome Aberrations; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D019175:DNA Methylation; D017931:DNA Primers; D005145:Face / Q000002:abnormalities*; D005260:Female; D006801:Humans; D007223:Infant; D007564:Japan; D008297:Male; D009154:Mutation; D010375:Pedigree; D013577:Syndrome; D000097584:DNA Methyltransferase 3B
chemical_list: D004248:DNA (Cytosine-5-)-Methyltransferases; D017931:DNA Primers; D000097584:DNA Methyltransferase 3B