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

Tassabehji, Mayada; Newton, Valeria E.; Read, Andrew P.

doi:10.1038/ng1194-251

Cited by 598 publications

(360 citation statements)

References 11 publications

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“…Mitf is a basic helix-loop-helix leucine zipper transcription factor involved in melanocyte and osteoclast development [19,20]. Loss of melanocytes due to Mitf mutation causes abnormality of the stria morphology and function, leading to hearing loss in both humans and mice [16,21,22]. Mitf mutation in humans is one of the causes of Waardenburg syndrome [23], a group of genetic conditions that can cause hearing loss and change in coloring of the hair, skin, and eyes [24].…”

Section: Introductionmentioning

confidence: 99%

Organ of Corti and Stria Vascularis: Is there an Interdependence for Survival?

Liu

Chen

et al. 2016

PLoS ONE

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Cochlear hair cells and the stria vascularis are critical for normal hearing. Hair cells transduce mechanical stimuli into electrical signals, whereas the stria is responsible for generating the endocochlear potential (EP), which is the driving force for hair cell mechanotransduction. We questioned whether hair cells and the stria interdepend for survival by using two mouse models. Atoh1 conditional knockout mice, which lose all hair cells within four weeks after birth, were used to determine whether the absence of hair cells would affect function and survival of stria. We showed that stria morphology and EP remained normal for long time despite a complete loss of all hair cells. We then used a mouse model that has an abnormal stria morphology and function due to mutation of the Mitf gene to determine whether hair cells are able to survive and transduce sound signals without a normal electrochemical environment in the endolymph. A strial defect, reflected by missing intermediate cells in the stria and by reduction of EP, led to systematic outer hair cell death from the base to the apex after postnatal day 18. However, an 18-mV EP was sufficient for outer hair cell survival. Surprisingly, inner hair cell survival was less vulnerable to reduction of the EP. Our studies show that normal function of the stria is essential for adult outer hair cell survival, while the survival and normal function of the stria vascularis do not depend on functional hair cells.

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Section: Introductionmentioning

confidence: 99%

Organ of Corti and Stria Vascularis: Is there an Interdependence for Survival?

Liu

Chen

et al. 2016

PLoS ONE

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“…We hypothesized that, among these genes, the prime candidate gene was the gene encoding the microphthalmia‐associated transcription factor ( MITF ) that has been shown to be associated with coat color, eye color and hearing disorder phenotypes, known as Waardenburg syndrome and Tietz syndrome in human (Tassabehji et al . 1994; Smith et al . 2000; reviewed in Pingault et al .…”

Section: Introductionmentioning

confidence: 99%

Microphthalmia‐associated transcription factor mutations are associated with white‐spotted coat color in swamp buffalo

et al. 2015

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SummaryA candidate gene analysis of the microphthalmia‐associated transcription factor (MITF) gene was used in an attempt to identify the genetic basis for a white‐spotted coat color phenotype in the Asian swamp buffalo (Bubalus bubalis carabanensis). Ninety‐three buffaloes—32 solid, 38 spotted and 23 white individuals—were Sanger‐sequenced for all MITF exons as well as highly conserved intronic and flanking regions. MITF cDNA representing skin and iris tissue from six spotted, nine solid and one white buffaloes was also Sanger‐sequenced to confirm detected mutations. Two independent loss‐of‐function mutations, a premature stop codon (c.328C>T, p.Arg110*) and a donor splice‐site mutation (c.840+2T>A, p.Glu281_Leu282Ins8), both of which cause white‐spotted coat color in swamp buffaloes, were identified. The nonsense mutation leads to a premature stop codon in exon 3, and likely removal of the resulting mRNA via nonsense‐mediated decay pathway, whereas the donor splice‐site mutation leads to aberrant splicing of exon 8 that encodes part of a highly conserved region of MITF. The resulting insertion of eight amino acid residues is expected to perturb the leucine zipper part in the basic helix‐loop‐helix leucine zipper (bHLH‐Zip) domain and will most likely influence dimerization and DNA binding capacity. Electrophoretic mobility shift assay was performed using mutant and wild‐type MITF proteins and showed that the mutant MITF protein resulting from the splice‐site mutation decreased in vitro DNA binding capacity compared to wild‐type MITF. White‐spotted buffalo bulls are sacrificed in funeral ceremonies in Tana Toraja, Indonesia, because they are considered holy, and our results show that genetic variation causes a tie to the cultural use of these buffaloes.

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“…In addition to defects in pigment cells of the skin, eye, hair follicles, and inner ear, severe dominant mutants of this gene also affected several other cell types such as bone resorbing osteoclasts, retinal pigment epithelial cells, and mast cells (Steingrı´msson et al, 1994). In humans, germline heterozygous mutations of the MITF gene are associated with the congenital pigmentation/ deafness condition, Waardenburg Syndrome (WS) type IIA (Hughes et al, 1994;Tassabehji et al, 1994;Nobukuni et al, 1996), in which affected individuals display variable degrees of pigmentation dilution and associated deafness because of melanocyte defects in the inner ear (for a review see Price and Fisher, 2001). The genetic traits that are observed in these human congenital disorders are because of loss of one allele of MITF, or expression of dominant-negative alleles as in Tietz syndrome.…”

Section: Genetics Of Mitf In the Pigment Cellsmentioning

confidence: 99%

Microphthalamia-associated transcription factor: a critical regulator of pigment cell development and survival

2003

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The microphthalamia-associated transcription factor (MITF) is an integral transcriptional regulator in melanocyte, the lineage from which melanoma cells originate. This basic-helix-loop-helix-leucine-zipper (bHLHzip) protein is critical for melanocyte cell-fate choice during commitment from pluripotent precursor cells in the neural crest. Its role in differentiation pathways has been highlighted by its potent transcriptional and lineage-specific regulation of the three major pigment enzymes: tyrosinase, Tyrp1, and Dct as well as other pigmentation factors. However, the cellular functions of MITF seem to be wider than differentiation and cell-fate pathways alone, since melanocytes and melanoma cells appear to require an expression of this factor. Here, we discuss the transcriptional networks in which MITF is thought to reside and describe signaling pathways in the cell which impinge on MITF. Accumulating evidence supports the notion that MITF is involved in survival pathways during normal development as well as during neoplastic growth of melanoma.

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

Cited by 598 publications

References 11 publications

Organ of Corti and Stria Vascularis: Is there an Interdependence for Survival?

Organ of Corti and Stria Vascularis: Is there an Interdependence for Survival?

Microphthalmia‐associated transcription factor mutations are associated with white‐spotted coat color in swamp buffalo

Microphthalamia-associated transcription factor: a critical regulator of pigment cell development and survival

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