Nucleic Acids Research, Vol 26, Issue 21 4888-4894, Copyright © 1998 by Oxford University Press
PP Van Sloun, SW Wijnhoven, HJ Kool, R Slater, G Weeda, AA van Zeeland, PH Lohman and H Vrieling
A mouse model was generated to investigate loss of heterozygosity (LOH)
events in somatic cells. The adenine phosphoribosyltransferase ( Aprt )
gene was disrupted in embryonic stem cells using a conventional gene
targeting approach and subsequently Aprt hetero-zygous and homozygous mice
were derived. Aprt homozygous deficient animals were viable though the
mendelian inheritance pattern was skewed. On average these mice died at 6
months of age from severe renal failure. In T-lymphocytes of Aprt
heterozygous mice the mean spontaneous mutant frequency at the Aprt locus
was 8.7 x 10(-6) while the frequency was 0.8 x 10(-6) at the hypoxanthine
phosphoribosyltransferase locus. In order to determine whether LOH events
contribute to the high spontaneous mutant frequency at the Aprt locus, 140
Aprt mutant T-lymphocyte clones were expanded and analysed by
allele-specific PCR. In 97 (69%) of these clones the wild-type allele had
been lost. Nine of the mutant clones were characterized in more detail
using dual-coloured fluorescence in situ hybridization analysis. Five out
of six of the mutant clones which arose from an LOH event, based on the PCR
assay, contained a duplication of the targeted allele. Therefore, mitotic
recombination or chromosome loss followed by duplication of the remaining
homologue appears to be the predominant mechanism for the in vivo
generation of Aprt mutant T-lymphocytes.
ARTICLES
Determination of spontaneous loss of heterozygosity mutations in Aprt heterozygous mice
Department of Radiation Genetics and Chemical Mutagenesis-MGC, Leiden University Medical Center, PO Box 9503, 2300 RA Leiden, The Netherlands.
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