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Waardenburg syndrome (WS)
2005-02-01
Carolina Vicente-Dueñas
,
Camino Bermejo-Rodríguez
,
María Pérez-Caro
,
Ines González-Herrero
,
Manuel Sánchez-Martín
,
Isidro Sánchez-García
Affiliation
Identity
Name
Waardenburg syndrome (WS)
Alias
Klein-Waardenburg syndrome (WS3) , Waardenburg syndrome with upper limb anomalies (WS3) , White forelock with malformations (WS3) , Waardenburg-Hirschsprung disease (WS4) , Waardenburg syndrome variant (WS4) , Shan-Waardenburg syndrome (WS4) , Hirschsprung disease with pigmentary anomaly (WS4)
Note
Waardenburg syndrome (WS) is an auditory-pigmentary syndrome caused by a deficiency of melanocytes and other neural crest-derived cells.
, The disease was named for Petrus Johannes Waardenburg, a Dutch ophthalmologist (1886-1979) who was the first to notice that people with two different coloured eyes frequently had hearing problems.
Inheritance
Inherited in an autosomal dominant manner with an incidence of 1 in 40 000 newborns. Almost 90% of patients have an affected parent but the symptoms in the parent can be quite different from those in the child.
Omim
148820 , 193500 , 193510 , 277580 , 600193 , 606662 , 608890 , 611584 , 613265 , 613266
Mesh
D014849
Orphanet
3440 Waardenburg syndrome
Umls
C0043008
Clinics
Note
Waardenburg syndrome (WS) is a hereditary auditory-pigmentary syndrome, the major symptoms being congenital sensorineural hearing loss and pigmentary disturbance of eyes, hair and skin. Depending in additional symptoms, WS can be classified into four types: WS type I (WS1) is associated with facial deformity such as dystopia canthorum (lateral displacement of the inner canthi); WS2 has no other symptoms; WS3 is associated with upper limb deformity; and WS4, with megacolon.
Phenotype and clinics
Disease with variable penetrance and several know clinical types. Characteristics may include depigmentation of the hair and skin, congenital deafness, heterochromia iridis, medial eyebrow hyperplasia, hypertrophy of the nasal root, and especially dystopia canthorum. The underlying cause may be defective development of the neural crest (neurocristopathy). Waardenburgs syndrome may be closely related to piebaldism. Klein-Waardenburg syndrome refers to a disorder that also includes upper limb abnormalities.
Neoplastic risk
Slight increased risk for rhabdomyosarcoma.
Treatment
No specific treatment is available for Waardenburg syndrome. Attention must be paid to any hearing deficit and hearing aids and appropriate schooling may need to be provided. Type 4 patients with constipation require special attention to their diet and medications to keep their bowels moving.
Prognosis
With correction of hearing deficits, affected people should be able to lead a normal life.
Genes involved and Proteins
Note
WS can be classified into four types. At least one gene responsible for each type of WS has been cloned and for these cloning procedures mice with pigmentation anomalies have contributed greatly. Six genes contributing to this syndrome-
PAX3
,
SOX10
,
MITF
,
SNAI2
,
EDN3
and
EDNRB
- have been cloned so far, all of them necessary for normal development of melanocytes.Table 1: Genes involved in Waardenburg syndrome (WS):
GENE
Syndrome
Specific symptoms
PAX3
WS1; WS3
Dysthopia canthorum, hypoplasia of limb muscle; contracture of elbows, fingers.
MITF
WS2
Main symptoms only (auditory-pigmentary syndrome)
SNAI2
WS2
Main symptoms only (auditory-pigmentary syndrome)
EDNRB
WS4
Hirschsprungs disease
EDN3
WS4
Hirschsprungs disease
SOX10
WS4
Hirschsprungs disease
Alias
PAIRED BOX GENE 3PAIRED DOMAIN GENE HuP2; HUP2PAX3\/FKHR FUSION GENEWS1
Note
PAX3 is an important gene in muscle development and muscle-producing neoplasms such as rhabdomyosarcomas.
Description
10 exons
Expression
is expressed during embryonic development. Skeletal muscle, esophagus, cerebellum, pancreas, liver and stomach.
Function
Transcription factor
Note
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.
Alias
SRY-BOX10SRY-RELATED HMG-BOX GEN 10DOMINANT MEGACOLON, MOUSE, HOMOLOG OF; DOM.
Description
5 exons
Note
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.
Description
466 residues
Expression
During development in cells of the neural crest.
Function
Transcription factor.
Note
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.
Alias
MICROPHTHALMIA-ASSOCIATED TRANSCRIPTION FACTORMICROPHTHALMIA, MOUSE, HOMOLOG OF
Description
9 exons
Note
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.
Description
520 residues
Expression
in melanocytes
Function
Transcription factor
Note
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.
Alias
SNAI2SLUGHNEURAL CREST TRANSCRIPTION FACTOR SLUG.
Description
3 exons
Note
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.
Description
268 residues
Expression
Placenta, adult heart, pancreas, liver, kidney and skeletal muscle.
Function
Transcriptional repressor.
Note
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.
Alias
ET3
Description
5 exons
Expression
trophoblasts, placental stem villi vessels.
Function
Peptide hormone.
Alias
ETB \/\/ ETRB
Description
7 exons
Expression
lung, placenta, kidney and skeletal muscle.
Function
G protein-coupled receptor.
Note
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.
Bibliography
Pubmed ID
Last Year
Title
Authors
10942418
2000
Interaction among SOX10, PAX3 and MITF, three genes altered in Waardenburg syndrome.
Bondurand N et al
11730045
2001
Waardenburg syndrome.
Konno P et al
11773966
2002
A mouse model of Waardenburg syndrome type 4 with a new spontaneous mutation of the endothelin-B receptor gene.
Matsushima Y et al
11434563
2001
EDNRB/EDN3 and Hirschsprung disease type II.
McCallion AS et al
12444107
2002
SLUG (SNAI2) deletions in patients with Waardenburg disease.
Sánchez-Martín M et al
10077527
1999
The Sox10(Dom) mouse: modeling the genetic variation of Waardenburg-Shah (WS4) syndrome.
Southard-Smith EM et al
10952390
2000
MITF: a stream flowing for pigment cells.
Tachibana M et al
12950719
2003
Mouse models for four types of Waardenburg syndrome.
Tachibana M et al
10762540
2000
Neurological phenotype in Waardenburg syndrome type 4 correlates with novel SOX10 truncating mutations and expression in developing brain.
Touraine RL et al
10938265
2000
Regulation of the microphthalmia-associated transcription factor gene by the Waardenburg syndrome type 4 gene, SOX10.
Verastegui C et al
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