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.
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- "Type 1 and 3 patients have a mutation of the PAX3 transcription factor gene (Tassabehji et al., 1992; Baldwin et al., 1992) and type 2 is due to a gene mutation lf micropthalmia associated transcription factor (MITF) (Tassabehji et at., 1994; Tachibana et al., 1994). Type IV patients have a heterozygous gene mutation of the SOX10 or homozygous mutations either in the Endothelin-3 (EDN3) or in the Endothelin B receptor (EDNR3) (Puffenberger et at., 1994; Mccallion & Chakravarti 2001). "
Article: Genetics of pigmentary disorders[Show abstract] [Hide abstract]
ABSTRACT: The genetic and molecular bases of various types of congenital pigmentary disorders have been classified in the past 10 years, as follows: (1) disorders of melanoblast migration in the embryo from the neural crest to the skin: piebaldism; Waardenburg syndrome 1-4 (WS1-WS4); dyschromatosis symmetrica hereditaria. (2) Disorders of melanosome formation in the melanocyte: Hermansky-Pudlak syndrome 1-7 (HPS1-7); Chediak-Higashi syndrome 1 (CHS1). (3) Disorders of melanin synthesis in the melanosome: oculocutaneous albinism 1-4 (OCA1-4). (4) Disorders of mature melanosome transfer to the tips of the dendrites Griscelli syndrome 1-3 (GS1-3). These disorders are presented and their gene mutations and pathogenesis are discussed.American Journal of Medical Genetics Part C Seminars in Medical Genetics 05/2013; 131C(1):75-81. DOI:10.1002/ajmg.c.30036 · 3.54 Impact Factor
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- "In particular, mutations having a wide range of effects on coat colour, from moderate spotting to complete absence of pigmentation, have been reported in mice (Steingrímsson et al. 2004; Levy et al. 2006), rat (Opdecamp et al. 1998), Syrian hamster (Hodgkinson et al. 1998; Graw et al. 2003), dogs (Rothschild et al. 2006; Karlsson et al. 2007) and Japanese quail (Minvielle et al. 2010). In humans, MITF gene mutations are responsible for Waardenburg syndrome type 2A (Tassabehji et al. 1994; Nobukuni et al. 1996). "
ABSTRACT: Candidate gene analysis, quantitative trait locus mapping in outbreed and experimental cross-populations and a genomewide association study in Holstein have reported that a few chromosome regions contribute to great variability in the degree of white/black spotting in cattle. In particular, an important region affecting this trait was localized on bovine chromosome 22 in the region containing the microphthalmia-associated transcription factor (MITF) gene. We sequenced a total of 7258 bp of the MITF gene in 40 cattle of different breeds, including 20 animals from spotted breeds (10 Italian Holstein and 10 Italian Simmental) and 20 animals from solid coloured breeds (10 Italian Brown and 10 Reggiana), and identified 17 single nucleotide polymorphisms (SNPs). The allele frequencies of one polymorphism (g.32386957A>T) were clearly different between spotted (A = 0.875; T = 0.125) and non-spotted breeds (A = 0.125; T = 0.875) (P = 8.2E-12). This result was confirmed by genotyping additional animals of these four breeds (P < 1.0E-20). A total of 21 different haplotypes were inferred from the sequenced animals. Considering similarities among haplotypes, spotted and non-spotted groups of cattle showed significant differences in their haplotype distribution (P = 0.001), which was further supported by the analysis of molecular variance (amova) of two genotyped SNPs in an enlarged sample of cattle. Variability in the MITF gene clearly explained the differences between spotted and non-spotted phenotypes but, at the same time, it is evident that this gene is not the only genetic factor determining piebaldism in Italian Holstein and Italian Simmental cattle breeds.Animal Genetics 06/2012; 43(3):250-6. DOI:10.1111/j.1365-2052.2011.02242.x · 2.21 Impact Factor
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- "MITF has been shown to be a major transcription factor in the regulation of melanogenesis by upregulating downstream target genes, such as tyrosinase  . MITF may play a key role not only in the control of differentiation, but also in melanocyte survival , and it is tempting to speculate that a continued inhibition of its expression by a sustained exposure to ROS may lead to melanocyte death, thus providing a molecular basis for the observed association between vitiligo and oxidative stress . Jimenez-Cervantes et al.  indeed showed that an inhibition of MITF expression reduced the expression of tyrosinase and has involved H 2 O 2 production in melanoma cells. "
ABSTRACT: How signaling via reactive oxygen species (ROS) influences skin pigmentation is unclear. We have investigated how NADPH oxidase-derived ROS modulates the expression of the key pigment "melanin" synthesizing enzymes in B16 mouse melanoma cells. A melanin inducer α-melanocyte-stimulating hormone (α-MSH) caused ROS generation that was inhibited by the NADPH oxidase inhibitor Diphenyleneiodonium (DPI) and was insensitive to antagonists of other ROS-producing enzyme systems including mitochondrial enzymes, cycloxygenase, and xanthine oxidase. NADPH oxidase 4 (Nox4) was found to be the most abundant isoform expressed in B16 cells, and its gene levels, as well as ROS generation, were enhanced by α-MSH. Interestingly, silencing Nox4 gene expression with Nox4 siRNA augmented melanin formation under basal conditions and after α-MSH stimulation, demonstrating that constitutive or stimulated Nox4-dependent ROS inhibits melanin formation. This process may be mediated by targeting the promoter region of a melanin synthesizing enzyme tyrosinase, because Nox4 siRNA enhanced tyrosinase promoter activity. Moreover, inhibition of tyrosinase mRNA expression in Nox4 siRNA-treated cells by blocking de novo mRNA and protein synthesis with actinomycin D and cycloheximide respectively indicates that Nox4 repression induces melanogenesis by increasing tyrosinase gene expression. We also found that α-MSH activated its downstream signal transducer microphthalmia-associated transcription factor (MITF) to stimulate Nox4 gene expression. We thus identified a novel mechanism by MITF signaling that in turn stimulates Nox4 to drive ROS generation, thereby repressing melanin synthesis. Such sequence of actions appears to act as an internal feedback mechanism to fine-tune melanin synthesis in response to exogenous challenges such as UV radiation.Free Radical Biology and Medicine 03/2012; 52(9):1835-43. DOI:10.1016/j.freeradbiomed.2012.02.040 · 5.71 Impact Factor