Impact of mismatch repair deficiency on genomic stability in the maternal germline and during early embryonic development.
The effects of lack of the mismatch repair protein PMS2 on germline and maternal-effect mutations were studied in transgenic mice that allow mutant cells to be visualized in situ. Tg(betaA-G11PLAP) mice are transgenic for the G11 allele of a human placental alkaline phosphatase (PLAP) gene driven by a human beta-actin promoter. The G11 allele of the PLAP gene does not produce enzyme due to a frameshift induced by a mononucleotide repeat containing 11 G:C basepairs. Loss of one G:C basepair restores enzyme production. When the G11 PLAP allele was passed through the germline of female mice lacking PMS2, approximately 25% of the offspring that inherited the transgene exhibited the phenotype expected for germline mutation. The mice transmitted the germline-mutation phenotype normally and their offspring exhibited PLAP enzyme activity in at least 30% of the cells in each tissue examined. By contrast, only 1 of 32 mice that inherited the G11 PLAP transgene from a wild-type male crossed to a Pms2-/- female exhibited a high number of PLAP+ cells. Compared to germline revertants, approximately one half to one quarter as many cells were PLAP+, suggesting that a mutation occurred in one cell of an embryo containing two to four cells. These data suggest that the paternally derived Pms2 gene provided normal levels of PMS2 protein to embryos by the time they reached the eight-cell stage, but that smaller embryos formed from PMS2-deficient eggs lacked PMS2 function.
Larson
Jon S
JS
Department of Molecular Genetics, Biochemistry and Microbiology, College of Medicine, University of Cincinnati, Cincinnati, OH 45267-0524, USA.
Stringer
Saundra L
SL
Stringer
James R
JR
D000469:Alkaline Phosphatase / Q000235:genetics; D000818:Animals; D020137:Base Pair Mismatch; D004260:DNA Repair; D047108:Embryonic Development / Q000235:genetics*; D005260:Female; D018392:Genomic Imprinting; D042822:Genomic Instability; D005854:Germ Cells; D006801:Humans; D008297:Male; D051379:Mice; D010920:Placenta / Q000201:enzymology
D000469:Alkaline Phosphatase