Human Molecular Genetics, 2002, Vol. 11, No. 25 3231-3236
© 2002 Oxford University Press
SLUG (SNAI2) deletions in patients with Waardenburg disease
1Instituto de Biología Molecular y Celular del Cáncer (IBMCC), Centro de Investigación del Cáncer, CSIC/Universidad de Salamanca, Campus Unamuno, 37007 Salamanca, Spain and 2Academic Unit of Medical Genetics, St Mary's Hospital, Manchester M13 0JH, UK
Received August 21, 2002; Accepted October 4, 2002
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.
* To whom correspondence should be addressed. Tel: +34 923238403; Fax: +34 923294813; Email: isg{at}usal.es
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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