PAIRED BOX GENE 3PAIRED DOMAIN GENE HuP2; HUP2PAX3\/FKHR FUSION GENEWS1

PAX3 is an important gene in muscle development and muscle-producing neoplasms such as rhabdomyosarcomas.

10 exons

is expressed during embryonic development. Skeletal muscle, esophagus, cerebellum, pancreas, liver and stomach.

Transcription factor

Mutations in PAX3, which encodes a paired homeodomain transcription factor, are responsible for Waardenburg syndrome 1 and 3. PAX3 was shown to bind and transactivate the MITF promoter, thereby demonstrating the role of PAX3 in the regulation of MITF expression. This observation supports an epistatic relationship between MITF and PAX3 and can explain the pigmentary disorders observed in WS1 and 3, because MITF controls melanocyte development.
PAX3 defects affect neural crest cell derivatives, resulting in the presence of craneofacial malformations.

SRY-BOX10SRY-RELATED HMG-BOX GEN 10DOMINANT MEGACOLON, MOUSE, HOMOLOG OF; DOM.

5 exons

SOX10, a protein that modulates other transcription factors (including PAX3) belongs to the high mobility group (HMG) box superfamily of DNA-binding proteins. It is first expressed during development in cells of the neural crest that contributes to the forming peripheral nervous system, and can be detected in the sensory, sympathetic and enteric ganglia and along nerves. SOX10 is also transiently expressed in melanoblast.

466 residues

During development in cells of the neural crest.

Transcription factor.

Mutations in Sox10 also result in WS4.
How mutations in this gene lead to deafness and pigmentary abnormalities, shared by all the WS subtypes, was not elucidated. It was tempting to propose that the WS4 genes are directly or indirectly involved in the regulation of MITF expression that is crucial for melanocyte development.
SOX10 binds and transactivates the MITF promoter, whereas Sox10 mutants found in WS4 patients failed to stimulate the MITF promoter. Thus, there is an epistatic relationship between SOX1 and MITF, thereby giving a molecular basis for the audio-pigmentary defect in patients with WS4.
SOX10 joins Pax3, CREB and LEF1 in the list of transcription factors that control MITF expression.

MICROPHTHALMIA-ASSOCIATED TRANSCRIPTION FACTORMICROPHTHALMIA, MOUSE, HOMOLOG OF

9 exons

Microphtalmia-associated transcription factor (MITF) is a basic helix-loop-helix, leucin zipper transcription factor that plays a pivotal role in survival and differentiation of melanocytes, the cells that produce melanin pigments. MITF has been demonstrated to up-regulate the expression of the genes involved in melanin synthesis, such as tyrosine, TRP1, and TRP2. Further MITF is thought to be a master gene in melanocyte differentiation, because its forced expression in fibroblast leads to the expression of melanocytes-specific enzymes required for melanin synthesis.

520 residues

in melanocytes

Transcription factor

In humans, mutations, of MITF are responsible for Waardenburg syndrome (WS) type 2, characterized by pigmentation abnormalities and sensorineural deafness due to the absence of melanocytes from the stria vascularis of the inner ear.
In mice, mutations in the microphthalmia gene cause pigmentation disorders because of the absence of melanocytes, supporting the involvement of MITF in melanocyte survival.
Over 20 different Mitf mutations have been described in mice. They all result in a deficiency in skin or coat melanocytes ranging in severity from minor pigmentary defects with normal eyes to total lack of coat and eye pigmentation, small colobomatous eyes, deafness and in some instances osteopetrosis.

SNAI2SLUGHNEURAL CREST TRANSCRIPTION FACTOR SLUG.

3 exons

SLUG a zinc finger transcription factor is a marker of neural crest cells in Xenopus, zebrafish and chick embryos and probably has a functional role in formation of premigratory neural crest. In the mouse, the corresponding gene, Slugh, is expressed in migratory but not premigratory neural crest cells and is not essential for neural crest development.

268 residues

Placenta, adult heart, pancreas, liver, kidney and skeletal muscle.

Transcriptional repressor.

Mice lacking Slugh have patchy deficiency of melanocytes, a phenotype similar to human Waardenburg syndrome. It has been shown that some human patients with Waardenburg syndrome carry homozygous deletions of SLUG as their only detected genetic abnormality, thus defining a recesive form of type 2 WS. Preliminary investigations of the role of SLUG in melanocyte development show that it is a downstream target of MITF, which acts on an E-box sequence in the SLUG promoter.

ET3

5 exons

trophoblasts, placental stem villi vessels.

Peptide hormone.

ETB \/\/ ETRB

7 exons

lung, placenta, kidney and skeletal muscle.

G protein-coupled receptor.

WS4 is also caused by mutations in endothelin B receptor or in endothelin 3.
How mutations in these genes lead to deafness and pigmentary abnormalities, shared by all the WS subtypes, was not elucidated. It was tempting to propose that the WS4 genes are directly or indirectly involved in the regulation of MITF expression that is crucial for melanocyte development.