Disease relevance of Waardenburg's Syndrome

• We have determined that PAX3 (found previously to be mutated in Waardenburg syndrome) is the chromosome 2 locus rearranged by the t(2;13)(q35;q14) translocation of the paediatric solid tumour alveolar rhabdomyosarcoma [1].
• Recently, mutations in the human mi gene (MITF) were found in patients with Waardenburg Syndrome type 2 (WS2), a dominantly inherited syndrome associated with hearing loss and pigmentary disturbances [2].
• The transcription factor Sox10 is genetically linked with Waardenburg syndrome 4 (WS4) in humans and the Dominant megacolon (Dom) mouse model for this disease [3].
• Splotch locus mouse mutants: models for neural tube defects and Waardenburg syndrome type I in humans [4].
• In humans, MITF mutations cause Waardenburg syndrome type 2A (WS2A) and Tietz syndrome, autosomal dominant disorders resulting in deafness and hypopigmentation [5].

High impact information on Waardenburg's Syndrome

• Epistatic relationship between Waardenburg syndrome genes MITF and PAX3 [6].
• Here, we describe a mutation of the human gene for endothelin 3 (EDN3), homozygously present in a patient with a combined Waardenburg syndrome type 2 (WS2) and HSCR phenotype (Shah-Waardenburg syndrome) [7].
• Genes responsible for syndromic forms of hearing loss include the COL4A5 gene in Alport syndrome and the PAX3 and MITF genes in Waardenburg syndrome [8].
• Normal hearing in Splotch (Sp/+), the mouse homologue of Waardenburg syndrome type 1 [9].
• Waardenburg syndrome is an autosomal dominant disorder characterized by sensorineural deafness and pigmentary disturbances [10].

Chemical compound and disease context of Waardenburg's Syndrome

• A patient with Waardenburg syndrome had, in addition to the classical findings, a semidilated fixed pupil which did not react to changes of illumination, to convergence, or to pilocarpine of phospholine iodide [11].

Biological context of Waardenburg's Syndrome

• Assignment of the locus for Waardenburg syndrome type I to human chromosome 2q37 and possible homology to the Splotch mouse [12].
• Ser298 of MITF, a mutation site in Waardenburg syndrome type 2, is a phosphorylation site with functional significance [13].
• These mutations confirm that Waardenburg syndrome is produced by gene dosage effects and show that the phenotypic differences between Splotch mice and humans with Waardenburg syndrome are caused by differences in genetic background rather than different primary effects of the mutations [14].
• Point mutation in the MITF gene causing Waardenburg syndrome type II in a three-generation Indian family [15].
• Genomic DNA from probands of various Waardenburg syndrome (WS) families were PCR-amplified using primers flanking the 8 exons of PAX3 [16].

Anatomical context of Waardenburg's Syndrome

• SRY-related HMG box-containing factor 10 (SOX10) is a transcription factor essential for neural crest development and differentiation, and involved in Waardenburg syndrome type IV and PCWH syndrome [17].
• Loss-of-function mutations of Pax3 in Splotch mice and in Waardenburg syndrome in man revealed that Pax3 is necessary for the proper formation of caudal neural crest derivatives and for the migration of myoblasts into the limb [18].
• MITF has been found mutated in patients with Waardenburg syndrome 2A, and plays a crucial role in melanocyte development [19].
• Since its discovery as a mutant allele producing mice devoid of viable melanocytes, Mi has emerged as the gene whose mutation is responsible for the human pigmentation condition Waardenburg Syndrome IIa, as well as a variety of cellular defects involving retinal pigment epithelium, osteoclasts, and mast cells [20].
• Spiral ganglion agenesis and midline congenital anomalies are common features in Waardenburg syndrome [21].

Gene context of Waardenburg's Syndrome

• One example is Waardenburg syndrome that can be caused by mutations in the PAX3, SOX10 or MITF genes [22].
• Regulation of the microphthalmia-associated transcription factor gene by the Waardenburg syndrome type 4 gene, SOX10 [23].
• Novel EDNRB mutations have been detected in non-syndromic HD patients with heterozygous forms, and homozygous mutations of the EDNRB or the EDN3 genes have been reported in HD patients associated with type 2 Waardenburg syndrome [24].
• The human homologue of MITF is mutated in patients with the pigmentary and deafness disorder Waardenburg Syndrome Type 2A (WS2A) [25].
• Effects of Pax3 modifier genes on craniofacial morphology, pigmentation, and viability: a murine model of Waardenburg syndrome variation [26].

Analytical, diagnostic and therapeutic context of Waardenburg's Syndrome

• The Waardenburg syndrome type 4 gene, SOX10, is a novel tumor-associated antigen identified in a patient with a dramatic response to immunotherapy [27].
• Mutation in intron 6 of the hamster Mitf gene leads to skipping of the subsequent exon and creates a novel animal model for the human Waardenburg syndrome type II [28].

References