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

* Mammalian Development Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, {dagger} Biochemistry and Molecular Biology, Faculty of Medicine, University of Iceland, 101 Reykjavík, Iceland and {ddagger} 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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