SLUG (SNAI2) deletions in patients with Waardenburg disease

Hum Mol Genet. 2002 Dec 1;11(25):3231-6. doi: 10.1093/hmg/11.25.3231.


Waardenburg syndrome (WS; deafness with pigmentary abnormalities) is a congenital disorder caused by defective function of the embryonic neural crest. Depending on additional symptoms, WS is classified into four types: WS1, WS2, WS3 and WS4. WS1 and WS3 are caused by mutations in PAX3, whereas WS2 is heterogenous, being caused by mutations in the microphthalmia (MITF) gene in some but not all affected families. The identification of Slugh, a zinc-finger transcription factor expressed in migratory neural crest cells, as the gene responsible for pigmentary disturbances in mice prompted us to analyse the role of its human homologue SLUG in neural crest defects. Here we show that two unrelated patients with WS2 have homozygous deletions in SLUG which result in absence of the SLUG product. We further show that Mitf is present in Slug-deficient cells and transactivates the SLUG promoter, and that Slugh and Kit genetically interact in vivo. Our findings further define the locus heterogeneity of WS2 and point to an essential role of SLUG in the development of neural crest-derived human cell lineages: its absence causes the auditory-pigmentary symptoms in at least some individuals with WS2.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adolescent
  • Animals
  • Child, Preschool
  • DNA-Binding Proteins / genetics
  • Female
  • Gene Deletion*
  • Gene Expression Regulation, Developmental / genetics
  • Humans
  • Male
  • Mice
  • Mice, Congenic
  • Mice, Mutant Strains
  • Microphthalmia-Associated Transcription Factor
  • Neural Crest / chemistry
  • Neural Crest / metabolism
  • Promoter Regions, Genetic / genetics
  • Proto-Oncogene Proteins c-kit / genetics
  • Snail Family Transcription Factors
  • Transcription Factors / deficiency
  • Transcription Factors / genetics*
  • Waardenburg Syndrome / genetics*
  • Zebrafish Proteins*


  • DNA-Binding Proteins
  • MITF protein, human
  • Microphthalmia-Associated Transcription Factor
  • Mitf protein, mouse
  • SNAI1 protein, human
  • SNAI2 protein, human
  • Snai2 protein, mouse
  • Snail Family Transcription Factors
  • Transcription Factors
  • Zebrafish Proteins
  • snai1b protein, zebrafish
  • Proto-Oncogene Proteins c-kit