Waardenburg syndrome type 2 caused by mutations in the human microphthalmia (MITF) gene.

Department of Medical Genetics, St. Mary's Hospital, Manchester, UK.
Nature Genetics (Impact Factor: 35.21). 12/1994; 8(3):251-5. DOI: 10.1038/ng1194-251
Source: PubMed

ABSTRACT Waardenburg syndrome type 2 (WS2) is a dominantly inherited syndrome of hearing loss and pigmentary disturbances. We recently mapped a WS2 gene to chromosome 3p12.3-p14.1 and proposed as a candidate gene MITF, the human homologue of the mouse microphthalmia (mi) gene. This encodes a putative basic-helix-loop-helix-leucine zipper transcription factor expressed in adult skin and in embryonic retina, otic vesicle and hair follicles. Mice carrying mi mutations show reduced pigmentation of the eyes and coat, and with some alleles, microphthalmia, hearing loss, osteopetrosis and mast cell defects. Here we show that affected individuals in two WS2 families have mutations affecting splice sites in the MITF gene.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The white spotting locus (S) in dogs is colocalized with the MITF (microphtalmia-associated transcription factor) gene. The phenotypic effects of the four S alleles range from solid colour (S) to extreme white spotting (sw). We have investigated four candidate mutations associated with the sw allele, a SINE insertion, a SNP at a conserved site and a simple repeat polymorphism all associated with the MITF-M promoter as well as a 12 base pair deletion in exon 1B. The variants associated with white spotting at all four loci were also found among wolves and we conclude that none of these could be a sole causal mutation, at least not for extreme white spotting. We propose that the three canine white spotting alleles are not caused by three independent mutations but represent haplotype effects due to different combinations of causal polymorphisms. The simple repeat polymorphism showed extensive diversity both in dogs and wolves, and allele-sharing was common between wolves and white spotted dogs but was non-existent between solid and spotted dogs as well as between wolves and solid dogs. This finding was unexpected as Solid is assumed to be the wild-type allele. The data indicate that the simple repeat polymorphism has been a target for selection during dog domestication and breed formation. We also evaluated the significance of the three MITF-M associated polymorphisms with a Luciferase assay, and found conclusive evidence that the simple repeat polymorphism affects promoter activity. Three alleles associated with white spotting gave consistently lower promoter activity compared with the allele associated with solid colour. We propose that the simple repeat polymorphism affects cooperativity between transcription factors binding on either flanking sides of the repeat. Thus, both genetic and functional evidence show that the simple repeat polymorphism is a key regulator of white spotting in dogs.
    PLoS ONE 01/2014; 9(8):e104363. · 3.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Heart failure is a leading cause of death in aging population. Cardiac hypertrophy is an adaptive reaction of the heart against cardiac overloading, but continuous cardiac hypertrophy is able to induce heart failure. We found that the level of miR-541 was decreased in angiotensin II (Ang-II) treated cardiomyocytes. Enforced expression of miR-541 resulted in a reduced hypertrophic phenotype upon Ang-II treatment in cellular models. In addition, we generated miR-541 transgenic mice that exhibited a reduced hypertrophic response upon Ang-II treatment. Furthermore, we found miR-541 is the target of microphthalmia-associated transcription factor (MITF) in the hypertrophic pathway and MITF can negatively regulate the expression of miR-541 at the transcriptional levels. MITF(ce/ce) mice exhibited a reduced hypertrophic phenotype upon Ang-II treatment. Knockdown of MITF also results in a reduction of hypertrophic responses after Ang-II treatment. Knockdown of miR-541 can block the antihypertrophic effect of MITF knockdown in cardiomyocytes upon Ang-II treatment. This indicates that the effect of MITF on cardiac hypertrophy relies on the regulation of miR-541. Our present study reveals a novel cardiac hypertrophy regulating pathway that was composed of miR-541 and MITF. Modulation of their levels may provide a new approach for tackling cardiac hypertrophy.
    Cell Death & Disease 04/2014; 5:e1171. · 6.04 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: mi transcription factor (MITF) is important in regulating the differentiation of mast cells. In particular, MITF regulates the transcription of the mouse mast cell-specific serine protease (mMCP)-6 gene, which is generally expressed by the connective tissue-type of mast cells. In this study, we investigated alternative isoforms of MITF that regulate transcription of the mMCP-6 gene in bone marrow-derived cultured mast cells in mice. The expression of MITF isoforms was examined by RT-PCR. We observed that MITF-A, -E, -H and -Mc were expressed by mucosal-type mast cells cultured in the presence of IL-3, whereas the connective tissue-type mast cells cultured in the presence of stem cell factor (SCF) expressed MITF-A. Overexpression of MITF isoforms increased luciferase activity through the mMCP-6 promoter in NIH-3T3 cells and elevated the level of mMCP-6 expression in the MC/9 mast cell line. Moreover, mMCP-6 expression in mast cells was significantly inhibited by the depletion of MITF. The transcriptional activity and DNA binding of MITF-A was comparable to that of MITF isoforms, including MITF-E, -H, and -Mc. Our results therefore suggest that MITF-A may be an important isoform of MITF in regulating the transcription of mMCP-6 in mouse connective tissue mast cells.
    Journal of Life Science. 01/2008; 18(10).