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SLUG (SNAI2) deletions in patients with Waardenburg disease
Manuel Sánchez-Martín1, Arancha Rodríguez-García, Jesús Pérez-Losada
1Instituto de Biología Molecular y Celular del Cáncer (IBMCC), Centro de Investigación del Cáncer, CSIC/Universidad de Salamanca, Campus Unamuno, 37007 Salamanca, Spain.
Abstract:
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.
Insights
Waardenburg syndrome type 2 (WS2) can result from SLUG gene deletions, impacting neural crest development. This finding clarifies WS2 causes and highlights SLUG
Area of Science:
- Developmental Biology
- Genetics
- Human Disease
Background:
- Waardenburg syndrome (WS) is a congenital disorder affecting neural crest development, leading to auditory and pigmentary abnormalities.
- WS is classified into four types (WS1-WS4), with WS2 exhibiting genetic heterogeneity, previously linked to MITF gene mutations in some cases.
Observation:
- The mouse gene Slugh, a transcription factor in neural crest cells, was investigated for its role in human WS2.
- Two unrelated WS2 patients were found to have homozygous deletions in the human SLUG gene, resulting in absent SLUG protein.
Findings:
- SLUG gene deletions cause the auditory-pigmentary symptoms observed in at least some individuals with WS2.
- Mitf protein is present in Slug-deficient cells and can transactivate the SLUG promoter.
- Slugh and Kit genes demonstrate genetic interaction in vivo, further elucidating the pathway.
Implications:
- These findings expand the understanding of WS2 locus heterogeneity.
- The study underscores the critical role of the SLUG gene in the development of human neural crest-derived cell lineages.
- Identifying SLUG deletions as a cause of WS2 provides new diagnostic and research avenues for this congenital disorder.
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