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Genetics, Vol. 178, 259-272, January 2008, Copyright © 2008
doi:10.1534/genetics.107.081893
An Unstable Targeted Allele of the Mouse Mitf Gene With a High Somatic and Germline Reversion Rate
Keren Bismuth*,1,
Susan Skuntz*,
Jón H. Hallsson
,
Evgenia Pak
,
Amalia S. Dutra,
Eiríkur Steingrímsson and
Heinz Arnheiter*,2
* Mammalian Development Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, Biochemistry and Molecular Biology, Faculty of Medicine, University of Iceland, 101 Reykjavík, Iceland and Genetic Diseases Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892
2 Corresponding author: Mammalian Development Section, Porter Neuroscience Research Center, 35 Convent Dr., MSC 3706, Bethesda, MD 20892-3706.
E-mail: ha3p{at}nih.gov
The mouse Mitf gene encodes a transcription factor that is regulated by serine phosphorylation and is critical for the development of melanin-containing pigment cells. To test the role of phosphorylation at a particular serine, S73 in exon 2 of Mitf, we used a standard targeting strategy in mouse embryonic stem cells to change the corresponding codon into one encoding an alanine. By chance, we generated an allele in which 85,222 bp of wild-type Mitf sequence are duplicated and inserted into an otherwise correctly targeted Mitf gene. Depending on the presence or absence of a neomycin resistance cassette, this genomic rearrangement leads to animals with a white coat with or without pigmented spots or a gray coat with obligatory white and black spots. Several independent, genetically stable germline revertants that lacked the duplicated wild-type sequence but retained the targeted codon were then derived. These animals were normally pigmented, indicating that the serine-to-alanine mutation is not deleterious to melanocyte development. The fact that mosaic coat reversions occur in all mice lacking the neo-cassette and that 
1% of these transmit a reverted allele to their offspring places this mutation among those with the highest spontaneous reversion rates in mammals.
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