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Wen B.,Developmental Cell Biology and Disease Program | Wen B.,Wenzhou Medical College | Chen Y.,Developmental Cell Biology and Disease Program | Chen Y.,Wenzhou Medical College | And 10 more authors.
Pigment Cell and Melanoma Research | Year: 2010

The tyrosine kinase receptor KIT and the transcription factor MITF, each required for melanocyte development, have been shown to interact functionally both in vitro and in vivo. In vitro, KIT signaling leads to MITF phosphorylation, affecting MITF activity and stability. In vivo, the presence of the MitfMi-wh allele exacerbates the spotting phenotype associated with heterozygosity for Kit mutations. Here, we show that among a series of other Mitf alleles, only the recessive Mitfmi-bws mimics the effect of MitfMi-wh on Kit. Intriguingly, Mitfmi-bws is characterized by a splice defect that leads to a reduction of RNAs containing MITF exon 2B which encodes serine-73, a serine phosphorylated upon KIT signaling. Nevertheless, other Mitf alleles that generally affect Mitf RNA levels, or carry a serine-73-to-alanine mutation that specifically reduces exon 2B-containing RNAs, do not show similar interactions with Kit in vivo. We conclude that the recessive Mitfmi-bws is a complex allele that can display a semi-dominant effect when present in a Kit-sensitized background. We suggest that human disease variability may equally be due to complex, allele-specific interactions between different genes. © 2010 John Wiley & Sons A/S. Source

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