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Novel mutations of SOX10 suggest a dominant negative role in Waardenburg-Shah syndrome
  1. Mai Har Shama,
  2. Vincent Chi Hang Luib,
  3. Benedict Ling Sze Chenb,
  4. Ming Fub,
  5. Paul Kwong Hang Tamb
  1. aDepartment of Biochemistry, The University of Hong Kong, Pokfulam, Hong Kong SAR, China, bDivision of Paediatric Surgery, Department of Surgery, University of Hong Kong Medical Centre, Queen Mary Hospital, Hong Kong SAR, China
  1. Professor Tam,paultam{at}

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Editor—Waardenburg syndrome (OMIM 193500) is a rare disorder (1 in 40 000 live births) characterised by distinctive facial features, pigmentary disturbance (white forelock, heterochromia iridis, white eyelashes, leucoderma), and cochlear deafness.1 Waardenburg-Shah syndrome combines the features of Waardenburg syndrome and Hirschsprung's disease (also called Waardenburg-Hirschsprung disease, Waardenburg syndrome type IV, WS4) (OMIM 277580). In addition to having white forelock, eyebrows, and eyelashes, the patients present in the neonatal period with intestinal obstruction, characteristic of Hirschsprung's disease.2-4 Mutations in three different genes have been identified in WS4 patients. These genes include the endothelin-B receptor gene (EDNRB),5 the gene for its ligand endothelin-3 (EDN3),6 7 and theSOX10 gene. It has been observed that heterozygous mutations of EDNRB orEDN3 are found in Hirschsprung's disease alone8-12 and only homozygous mutations of either gene are found in WS4. Therefore, when resulting fromEDN3 or EDNRBmutations, WS4 is inherited as an autosomal recessive trait.

Among the WS4 patients studied so far, 10 out of 37 have been reported to have had SOX10mutations.13-16 Interestingly, whenSOX10 mutations are involved, WS4 is inherited as an autosomal dominant condition. The presence ofSOX10 mutations in the Waardenburg-Shah patients suggest that the SOX10 gene could be involved in regulatory and signalling pathways for the normal development of the neural crest cell lineages which differentiate into melanocytes and enteric ganglia. The involvement ofSox10 in the development of enteric neurones has also been reported in the Dom(Dominant megacolon) mouse model of Hirschsprung's disease. It was shown that a single base insertion in the mouse Sox10 gene was responsible for the megacolon phenotype of the Dommutant.17 18 Interestingly, in the Waardenburg-Shah patients as well as the Dom mutant mouse model, the intestinal aganglionosis phenotype appears to …

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