PMID- 10469597
OWN - NLM
STAT- MEDLINE
DCOM- 19991223
LR  - 20190728
IS  - 0960-9822 (Print)
IS  - 0960-9822 (Linking)
VI  - 9
IP  - 16
DP  - 1999 Aug 26
TI  - Mutator phenotypes of common polymorphisms and missense mutations in MSH2.
PG  - 907-10
AB  - Hereditary non-polyposis colorectal cancer (HNPCC) is associated with germline
      mutations in the DNA mismatch repair gene hMSH2 [1], the human homologue of the
      Escherichia coli MutS gene. These are mostly nonsense, frameshift or deletion
      mutations that result in loss of intact protein and complete inactivation of DNA 
      mismatch repair. However, cancer is also associated with hMSH2 missense mutations
      that are merely inferred to be deleterious because they result in
      non-conservative substitutions of amino acids that are highly conserved among
      MutS family proteins. Moreover, sequence polymorphisms exist in hMSH2 that also
      change conserved amino acids but whose functional consequences and relationship
      to cancer are uncertain. Here, we show that yeast strains harboring putative
      equivalents of three hMSH2 polymorphisms have elevated mutation rates. Mutator
      effects were also observed for yeast equivalents of hMSH2 missense mutations
      found in HNPCC families and in an early onset colon tumor. Several distinct
      phenotypes were observed, indicating that these missense mutations have
      differential effects on MSH2 function(s). The results suggest that cancer may be 
      associated with even partial loss of hMSH2 function and they are consistent with 
      the hypothesis that polymorphisms in hMSH2 might predispose humans to disease.
FAU - Drotschmann, K
AU  - Drotschmann K
AD  - Laboratory of Molecular Genetics, National Institute of Environmental Health
      Sciences, Research Triangle Park, North Carolina 27709, USA.
FAU - Clark, A B
AU  - Clark AB
FAU - Kunkel, T A
AU  - Kunkel TA
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Curr Biol
JT  - Current biology : CB
JID - 9107782
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Fungal Proteins)
RN  - 0 (Proto-Oncogene Proteins)
RN  - EC 3.6.1.3 (MSH2 protein, human)
RN  - EC 3.6.1.3 (Msh2 protein, mouse)
RN  - EC 3.6.1.3 (Msh2 protein, rat)
RN  - EC 3.6.1.3 (MutS Homolog 2 Protein)
SB  - IM
MH  - Amino Acid Sequence
MH  - Animals
MH  - Colorectal Neoplasms, Hereditary Nonpolyposis/genetics
MH  - DNA-Binding Proteins/genetics
MH  - Fungal Proteins/genetics
MH  - Humans
MH  - Mice
MH  - Molecular Sequence Data
MH  - MutS Homolog 2 Protein
MH  - Mutation, Missense/*genetics
MH  - Phenotype
MH  - Polymorphism, Genetic/*genetics
MH  - Proto-Oncogene Proteins/*genetics
MH  - Rats
MH  - Sequence Alignment
MH  - Yeasts
EDAT- 1999/09/02 00:00
MHDA- 1999/09/02 00:01
CRDT- 1999/09/02 00:00
PHST- 1999/09/02 00:00 [pubmed]
PHST- 1999/09/02 00:01 [medline]
PHST- 1999/09/02 00:00 [entrez]
AID - S0960-9822(99)80396-0 [pii]
AID - 10.1016/s0960-9822(99)80396-0 [doi]
PST - ppublish
SO  - Curr Biol. 1999 Aug 26;9(16):907-10. doi: 10.1016/s0960-9822(99)80396-0.