Waardenburg syndrome type 2 caused by mutations in the human microphthalmia (MITF) gene.
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.
[Show abstract] [Hide abstract]
ABSTRACT: Dietary intake of cadmium is inevitable, causing age-related increase in cadmium accumulation in many organs, including hair, choroid and retinal pigment epithelium (RPE). Cadmium has been implicated in the pathogenesis of hearing loss and macular degeneration. The functions of cochlea and retina are maintained by melanocytes and RPE, respectively, and the differentiation of these pigment cells is regulated by microphthalmia-associated transcription factor (MITF). In the present study, we explored the potential toxicity of cadmium in the cochlea and retina by using cultured human melanocytes and human RPE cell lines. MITF consists of multiple isoforms, including melanocyte-specific MITF-M and widely expressed MITF-H. Levels of MITF-M protein and its mRNA in human epidermal melanocytes and HMV-II melanoma cells were decreased significantly by cadmium. In parallel with the MITF reduction, mRNA levels of tyrosinase, the key enzyme of melanin biosynthesis that is regulated by MITF-M, were also decreased. In RPE cells, however, the levels of total MITF protein, constituting mainly MITF-H, were not decreased by cadmium. We thus identify MITF-M as the molecular target of cadmium toxicity in melanocytes, thereby accounting for the increased risk of disability from melanocyte malfunction, such as hearing and vision loss among people with elevated cadmium exposure.Biochemical and Biophysical Research Communications 11/2014; 454(4). DOI:10.1016/j.bbrc.2014.10.141 · 2.28 Impact Factor
Article: The genetics of malignant melanomaFrontiers in Bioscience 01/2008; Volume(13):5071. DOI:10.2741/3065 · 4.25 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Twenty years ago the first familial melanoma susceptibility gene, CDKN2A, was identified. Two years later, another high penetrance gene, CDK4, was found to be responsible for melanoma development in some families. Progress in identifying new familial melanoma genes was subsequently slow; however, with the advent of next generation sequencing, a small number of new high penetrance genes have recently been uncovered. This approach has identified the lineage specific oncogene MITF as a susceptibility gene both in melanoma families and the general population, as well as the discovery of telomere maintenance as a key pathway underlying melanoma predisposition. Given these rapid recent advances, this approach seems likely to continue to pay dividends. Here we review the currently known familial melanoma genes, providing evidence that most additionally confer risk to other cancers, indicating that they are likely general tumour suppressor genes or oncogenes, which has significant implications for surveillance and screening.This article is protected by copyright. All rights reserved.Pigment Cell & Melanoma Research 11/2014; 28(2). DOI:10.1111/pcmr.12333 · 5.84 Impact Factor