SLUG (SNAI2) deletions in patients with Waardenburg disease

TLDR

Waardenburg syndrome is a congenital disorder of neural‑crest development, classified into four types, with WS1 and WS3 caused by PAX3 mutations and WS2 heterogeneously linked to MITF mutations. The study aimed to investigate the role of the human SLUG transcription factor in neural‑crest defects, prompted by its mouse counterpart Slugh. We identified homozygous deletions of SLUG in two WS2 patients that abolish SLUG protein, showed that Mitf is present and can transactivate the SLUG promoter, and demonstrated a genetic interaction between SLUG and Kit. These findings confirm SLUG’s essential role in neural‑crest‑derived lineages and explain how its loss causes the auditory‑pigmentary symptoms observed in some WS2 individuals.

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.