Three novel DNMT3B mutations in Japanese patients with ICF syndrome.
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.
Shirohzu
Hisao
H
Division of Human Genetics, Department of Integrated Genetics, National Institute of Genetics, Mishima, Japan.
Kubota
Takeo
T
Kumazawa
Azumi
A
Sado
Takashi
T
Chijiwa
Takahito
T
Inagaki
Kouichi
K
Suetake
Isao
I
Tajima
Shoji
S
Wakui
Keiko
K
Miki
Yuko
Y
Hayashi
Masatoshi
M
Fukushima
Yoshimitsu
Y
Sasaki
Hiroyuki
H
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
D004248:DNA (Cytosine-5-)-Methyltransferases; D017931:DNA Primers; D000097584:DNA Methyltransferase 3B