Mutations in DNA methyltransferase DNMT3B in ICF syndrome affect its regulation by DNMT3L

Zheng Hua Xie, Yan Nv Huang, Zhao Xia Chen, Arthur D. Riggs, Jian Ping Ding, Humaira Gowher, Albert Jeltsch, Hiroyuki Sasaki, Kenichiro Hata, Guo Liang Xu

Research output: Contribution to journalArticlepeer-review

46 Citations (Scopus)


Deficiency in DNA methyltransferase DNMT3B causes a recessive human disorder characterized by immunodeficiency, centromeric instability and facial anomalies (ICF) in association with defects in genomic methylation. The majority of ICF mutations are single amino acid substitutions in the conserved catalytic domain of DNMT3B, which are believed to impair its enzymatic activity directly. The establishment of intact genomic methylation patterns in development requires a fine regulation of the de novo methylation activity of the two related methyltransferases DNMT3A and DNMT3B by regulatory factors including DNMT3L which has a stimulatory effect. Here, we show that two DNMT3B mutant proteins with ICF-causing substitution (A766P and R840Q) displayed a methylation activity similar to the wild-type enzyme both in vitro and in vivo. However, their stimulation by DNMT3L was severely compromised due to deficient protein interaction. Our findings suggest that methylation defects in ICF syndrome may also result from impaired stimulation of DNMT3B activity by DNMT3L or other unknown regulatory factors as well as from a weakened basal catalytic activity of the mutant DNMT3B protein per se.

Original languageEnglish
Pages (from-to)1375-1385
Number of pages11
JournalHuman molecular genetics
Issue number9
Publication statusPublished - May 2006
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


Dive into the research topics of 'Mutations in DNA methyltransferase DNMT3B in ICF syndrome affect its regulation by DNMT3L'. Together they form a unique fingerprint.

Cite this