Mutation of the MITF gene in albinism-deafness syndrome (Tietz syndrome)

Amiel, Jeanne; Watkin, Peter; Tassabehji, Mayada; Read, Andrew P.; Winter, R M

doi:10.1097/00019605-199801000-00003

Cited by 95 publications

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“…MITF haploinsufficiency leads to Waardenburg syndrome type IIa, which is characterized by deafness and pigmentation defects caused by melanocyte loss in the inner ear and the skin (12). In addition, dominant-negative mutations in MITF are associated with another auditory-pigmentary disorder, Teitz syndrome (13,14) (reviewed in Ref. 15).…”

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confidence: 99%

Characterization of an ERK-binding Domain in Microphthalmia-associated Transcription Factor and Differential Inhibition of ERK2-mediated Substrate Phosphorylation

Molina

Grewal

Bardwell

2005

Journal of Biological Chemistry

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Signal transduction networks that regulate gene expression and metabolism are crucial for cell growth, differentiation, and survival. Accordingly, aspects of the pathology of many diseases result from defects in signaling pathways or the transcriptional responses they regulate (1).Many extracellular signals are transmitted to downstream targets by an evolutionarily conserved protein kinase cascade designated the mitogen-activated protein kinase (MAPK) 2 cascade. The MAPK (also known as extracellular-signal-regulated kinase, or ERK) cascade is a three-kinase module that transmits signals from cell-surface receptors to downstream targets through sequential phosphorylations (2). The MAPK is phosphorylated, and thereby activated, by an upstream MAPK/ERK kinase (MEK), which has previously been activated by a MEK kinase, such as the proto-oncoprotein Raf. To further propagate the signal, activated MAPKs phosphorylate other kinases such as RSK1 (3), which then regulate downstream effectors. In addition, MAPKs directly phosphorylate many key effectors, including the ubiquitous transcription factors Elk-1, Ets-1, and ATF-2 (4 -6).Tissue-specific transcription factors are also targets of MAPK phosphorylation and provide cell-type specificity to MAPK-regulated responses (7,8). The microphthalmia-associated transcription factor (MITF) is a tissue-specific MAPK substrate found in melanocytes. MITF is a master transcriptional regulator for melanocytes, coordinating the expression of genes involved in stem cell maintenance, differentiation, melanogenesis, and cell survival (9 -11). MITF haploinsufficiency leads to Waardenburg syndrome type IIa, which is characterized by deafness and pigmentation defects caused by melanocyte loss in the inner ear and the skin (12). In addition, dominant-negative mutations in MITF are associated with another auditory-pigmentary disorder, Teitz syndrome (13, 14) (reviewed in Ref. 15). MITF is also a potential target in the treatment of skin cancer, because it may impart a selective advantage to melanoma cells at low expression levels (16, 17), while having an antiproliferative effect at higher expression levels (18).During the differentiation of neural crest-derived melanocytes, activation of the c-Kit receptor tyrosine kinase by its ligand Steel factor initiates signaling through the Ras3 Raf3 MEK1/23 ERK1/2 cascade, resulting in the phosphorylation of MITF, and the consequent induction of genes involved in differentiation (e.g. p21 Cip1 (19)), melanogenesis (e.g. tyrosinase (20)), and melanocyte survival (e.g. Bcl2 (16)). ERK2 directly phosphorylates MITF on Ser 73 (21); MITF is also phosphorylated at Ser 409 by ERK-activated RSK1 (22). The dually phosphorylated MITF displays increased affinity for the transcriptional co-activator CREB-binding protein (23). Dually phosphorylated MITF is also targeted for ubiquitination and subsequent degradation, ensuring transient gene induction (22).The ability of MAPKs to effectively and specifically recognize their substrates is enhanced by their capacity t...

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confidence: 99%

Characterization of an ERK-binding Domain in Microphthalmia-associated Transcription Factor and Differential Inhibition of ERK2-mediated Substrate Phosphorylation

Molina

Grewal

Bardwell

2005

Journal of Biological Chemistry

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“…They all result in a deficiency in skin and ear melanocytes and in defects in eye size and pigmentation (24). Mutations of the MITF gene in humans are associated with Waardenburg syndrome type 2 (33,34) and albinism-deafness (Tietz) syndrome (2). MITF has been shown to activate the expression of melanocyte-specific genes such as TYR and TRP1 through an evolutionarily conserved 11-bp sequence termed the M-box (22).…”

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confidence: 99%

The Microphthalmia Transcription Factor (Mitf) Controls Expression of the Ocular Albinism Type 1 Gene: Link between Melanin Synthesis and Melanosome Biogenesis

Vetrini

Auricchio

et al. 2004

Molecular and Cellular Biology

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Melanogenesis is the process that regulates skin and eye pigmentation. Albinism, a genetic disease causing pigmentation defects and visual disorders, is caused by mutations in genes controlling either melanin synthesis or melanosome biogenesis. Here we show that a common transcriptional control regulates both of these processes. We performed an analysis of the regulatory region of Oa1, the murine homolog of the gene that is mutated in the X-linked form of ocular albinism, as Oa1's function affects melanosome biogenesis. We demonstrated that Oa1 is a target of Mitf and that this regulatory mechanism is conserved in the human gene. Tissue-specific control of Oa1 transcription lies within a region of 617 bp that contains the E-box bound by Mitf. Finally, we took advantage of a virus-based system to assess tissue specificity in vivo. To this end, a small fragment of the Oa1 promoter was cloned in front of a reporter gene in an adeno-associated virus. After we injected this virus into the subretinal space, we observed reporter gene expression specifically in the retinal pigment epithelium, confirming the cell-specific expression of the Oa1 promoter in the eye. The results obtained with this viral system are a preamble to the development of new gene delivery approaches for the treatment of retinal pigment epithelium defects.

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“…The three major pigmentation enzymes tyrosinase, TYRP1, and DCT, all contain consensus MITF DNA binding elements that are conserved across species and are thought to be transcriptional targets of MITF (6 -8). In humans, germline heterozygous MITF mutation produces the pigmentation-deafness condition Waardenburg Syndrome IIA (9) and Tietz syndrome (10,11), manifesting pigmentation disturbances and deafness due to inner ear melanocyte deficiency (12). Interestingly, MITF expression is usually (if not always) maintained in human melanoma specimens, and it is increasingly used as a histopathologic marker for melanoma diagnosis (13)(14)(15)(16)(17).…”

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confidence: 99%

Identification of Aim-1 as the underwhiteMouse Mutant and Its Transcriptional Regulation by MITF

Fisher

2002

Journal of Biological Chemistry

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Animal pigmentation mutants have provided rich models for the identification of genes modulating pathways from melanocyte development to melanoma. One mouse model is the underwhite locus, alleles of which manifest altered pigmentation of both eye and fur, sometimes in an age-dependent fashion. Here we show that the mouse homolog of a recently identified gene whose mutation produces Japanese gold-colored fish, medaka b, maps to the mouse underwhite locus. We identify distinct mutations of this gene, known as Aim-1, in three underwhite mouse alleles and find that structure/function differences correlate with recessive versus dominant inheritance. The human ortholog of AIM-1 was originally identified as a melanocyte-restricted antigen that is recognized by autologous T cells from a patient with melanoma. We also provide evidence that AIM-1 is transcriptionally modulated by MITF, a melanocyte-specific transcription factor essential to pigmentation and a clinical diagnostic marker in human melanoma. Although AIM-1 appears to reside downstream of MITF, chromatin immunoprecipitations do not reveal binding of MITF to a 5-flanking region containing histone 3 acetylation, indicating that MITF either acts indirectly on AIM-1 or it binds to a remote regulatory sequence. Nevertheless, MITF links AIM-1 expression and the underwhite phenotype to a transcriptional network central to pigmentation in mammals.

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Mutation of the MITF gene in albinism-deafness syndrome (Tietz syndrome)

Cited by 95 publications

References 0 publications

Characterization of an ERK-binding Domain in Microphthalmia-associated Transcription Factor and Differential Inhibition of ERK2-mediated Substrate Phosphorylation

Characterization of an ERK-binding Domain in Microphthalmia-associated Transcription Factor and Differential Inhibition of ERK2-mediated Substrate Phosphorylation

The Microphthalmia Transcription Factor (Mitf) Controls Expression of the Ocular Albinism Type 1 Gene: Link between Melanin Synthesis and Melanosome Biogenesis

Identification of Aim-1 as the underwhiteMouse Mutant and Its Transcriptional Regulation by MITF

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