PMID- 10588719
OWN - NLM
STAT- MEDLINE
DCOM- 20000105
LR  - 20190501
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 96
IP  - 25
DP  - 1999 Dec 7
TI  - The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency
      syndrome.
PG  - 14412-7
AB  - DNA methylation is an important regulator of genetic information in species
      ranging from bacteria to humans. DNA methylation appears to be critical for
      mammalian development because mice nullizygous for a targeted disruption of the
      DNMT1 DNA methyltransferase die at an early embryonic stage. No DNA
      methyltransferase mutations have been reported in humans until now. We describe
      here the first example of naturally occurring mutations in a mammalian DNA
      methyltransferase gene. These mutations occur in patients with a rare autosomal
      recessive disorder, which is termed the ICF syndrome, for immunodeficiency,
      centromeric instability, and facial anomalies. Centromeric instability of
      chromosomes 1, 9, and 16 is associated with abnormal hypomethylation of CpG sites
      in their pericentromeric satellite regions. We are able to complement this
      hypomethylation defect by somatic cell fusion to Chinese hamster ovary cells,
      suggesting that the ICF gene is conserved in the hamster and promotes de novo
      methylation. ICF has been localized to a 9-centimorgan region of chromosome 20 by
      homozygosity mapping. By searching for homologies to known DNA
      methyltransferases, we identified a genomic sequence in the ICF region that
      contains the homologue of the mouse Dnmt3b methyltransferase gene. Using the
      human sequence to screen ICF kindreds, we discovered mutations in four patients
      from three families. Mutations include two missense substitutions and a 3-aa
      insertion resulting from the creation of a novel 3' splice acceptor. None of the 
      mutations were found in over 200 normal chromosomes. We conclude that mutations
      in the DNMT3B are responsible for the ICF syndrome.
FAU - Hansen, R S
AU  - Hansen RS
AD  - Department of Medicine, University of Washington, Seattle, WA 98195, USA.
      supreme@u.washington.edu
FAU - Wijmenga, C
AU  - Wijmenga C
FAU - Luo, P
AU  - Luo P
FAU - Stanek, A M
AU  - Stanek AM
FAU - Canfield, T K
AU  - Canfield TK
FAU - Weemaes, C M
AU  - Weemaes CM
FAU - Gartler, S M
AU  - Gartler SM
LA  - eng
GR  - R01 HD016659/HD/NICHD NIH HHS/United States
GR  - GM52463/GM/NIGMS NIH HHS/United States
GR  - HD16659/HD/NICHD NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - EC 2.1.1.37 (DNA (Cytosine-5-)-Methyltransferases)
RN  - EC 2.1.1.37 (DNA methyltransferase 3B)
SB  - IM
MH  - Amino Acid Sequence
MH  - Animals
MH  - CHO Cells
MH  - *Chromosome Aberrations
MH  - Cricetinae
MH  - DNA (Cytosine-5-)-Methyltransferases/*genetics
MH  - DNA Methylation
MH  - Face/*abnormalities
MH  - Female
MH  - Humans
MH  - Immunologic Deficiency Syndromes/*genetics
MH  - Male
MH  - Molecular Sequence Data
MH  - *Mutation
PMC - PMC24450
EDAT- 1999/12/10 00:00
MHDA- 1999/12/10 00:01
CRDT- 1999/12/10 00:00
PHST- 1999/12/10 00:00 [pubmed]
PHST- 1999/12/10 00:01 [medline]
PHST- 1999/12/10 00:00 [entrez]
AID - 10.1073/pnas.96.25.14412 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 1999 Dec 7;96(25):14412-7. doi:
      10.1073/pnas.96.25.14412.