Alternative titles; symbols
HGNC Approved Gene Symbol: SNAI2
Cytogenetic location: 8q11.21 Genomic coordinates (GRCh38): 8:48,917,598-48,921,429 (from NCBI)
SNAI2, or SLUG, belongs to the Snail family of zinc finger transcription factors (see 604238) that share an evolutionarily conserved role in mesoderm formation in invertebrates and vertebrates. SNAI2 triggers epithelial-mesenchymal transitions and plays an important role in developmental processes (Perez-Mancera et al., 2007).
By searching databases for homologs of mouse Slug, followed by sequencing a chromosome 8 cosmid and RT-PCR of human lymphoblastoid total RNA and genomic DNA, Cohen et al. (1998) isolated the human SLUG gene. The deduced 268-amino acid protein has a calculated molecular mass of approximately 30 kD. It contains 5 zinc finger regions and shares 95% amino acid identity with mouse Slug. Northern blot analysis revealed a 2.2-kb SLUG transcript in placenta and adult heart, pancreas, liver, kidney, and skeletal muscle.
Using Northern blot analysis, Rhim et al. (1997) found that mouse Slug was expressed at 7 days postcoitum, with the signal intensity decreasing subsequent to 11 days postcoitum. They stated that the results were consistent with a role for Slug in mouse embryonic development.
Cohen et al. (1998) determined that the SLUG gene contains 3 exons and spans more than 4 kb.
By linkage analysis, Rhim et al. (1997) mapped the mouse Slug gene to chromosome 16. By somatic cell hybrid analysis, they assigned the human SLUG gene to chromosome 8. By study of radiation cell lines they showed that it is closely linked to marker D8S2090 at cM 66-69, corresponding to cytogenetic region 8q11. By radiation hybrid analysis, Cohen et al. (1998) mapped the SLUG gene to 8q, closely linked to D8S2090.
The molecular events involved in conversion of pluripotent epithelial derivatives into various neural crest derivatives require complex cellular and environmental interactions modulated by lineage-specific transcription factors. Rhim et al. (1997) described an important event in the development of neural crest-derived cells as the transition of epithelial to mesenchymal characteristics during emigration from the neural tube. The zinc finger protein Slug appears to play an important role in this transition (Savagner et al., 1997). Slug is a neurogenic transcription factor belonging to the Snail family in Drosophila melanogaster. Embryologic studies in chicken and frog demonstrated that Slug mRNA was expressed in the developing neural crest and in mesodermal cells emerging from the primitive streak (Nieto et al., 1994). Rhim et al. (1997) stated that indirect functional analyses with antisense oligonucleotides directed against Slug mRNA showed specific and transient developmental failures at early embryonic stages. These stages resulted in defects in the neural tube closure between the midbrain and cervical regions, block of the epithelial-mesenchymal transition in the neural crest, and in the emergence of mesoderm from the primitive streak.
The E2A (147141)-HLF (142385) fusion gene transforms human pro-B lymphocytes by interfering with an early step in apoptotic signaling. In a search for E2A-HLF-responsive genes, Inukai et al. (1999) identified the human SLUG gene. SLUG bears close homology to the CES1 protein of C. elegans, which acts downstream of CES2 in a neuron-specific cell death pathway. Consistent with the postulated role of CES1 as an antiapoptotic transcription factor, SLUG was found to be nearly as active as BCL2 (151430) and BCLXL (600039) in promoting the survival of IL3 (147740)-dependent murine pro-B cells deprived of the cytokine. Inukai et al. (1999) concluded that SLUG is an evolutionarily conserved transcriptional repressor whose activation by E2A-HLF promotes the aberrant survival and eventual malignant transformation of mammalian pro-B cells otherwise slated for apoptotic death.
Sanchez-Martin et al. (2002) showed that in mice the Mitf gene product (156845) was present in Slug-deficient cells and transactivated the Slug promoter. Crossbreeding of transgenic mice provided evidence that Slug and Kit (164920) genetically interact in vivo. Sanchez-Martin et al. (2002) concluded that SNAI2 plays an essential role in the development of neural crest-derived human cell lineages.
By analyzing embryonic Sox9 (608160)-null mice and using gain-of-function experiments, Cheung et al. (2005) determined that specification of trunk neural crest cells involves the coordinated activity of Sox9, Foxd3, and Slug. Each transcription factor appeared to regulate the acquisition of distinct neural crest cell properties, while the combined expression of Sox9, Slug, and Foxd3 induced cells to manifest all the principal transcriptional and morphologic characteristics of neural crest cells.
The observations of Gupta et al. (2005) indicated that part of the metastatic proclivity of melanoma (155600) is attributable to lineage-specific factors expressed in melanocytes and not in other cells types analyzed. Analysis of microarray data from human nevi showed that the expression pattern of Slug, a master regulator of neural crest cell specification and migration, correlates with those of other genes that are important for neural crest cell migrations during development. Moreover, Slug is required for the metastasis of the transformed melanoma cells. These findings indicated that melanocyte-specific factors present before neoplastic transformation can have a pivotal role in governing melanoma progression.
Wu et al. (2005) showed that Slug was induced by p53 (TP53; 191170) in irradiated mouse bone marrow cells and protected damaged cells from apoptosis by repressing p53-mediated transcription of Puma (BBC3; 605854), an antagonist of the antiapoptotic protein Bcl2 (151430). Mice deficient in both Slug and Puma survived doses of total body irradiation that lethally depleted hematopoietic progenitor populations in mice lacking only Slug. Wu et al. (2005) concluded that SLUG functions downstream of p53 in developing blood cells to prevent their apoptosis.
Using genetically engineered knockin reporter mouse lines, Ye et al. (2015) demonstrated that normal gland-reconstituting mammary stem cells residing in the basal layer of the mammary epithelium and breast tumor-initiating cells originating in the luminal layer exploit the paralogous epithelial-to-mesenchymal transition (EMT)-transcription factors Slug and Snail (604238), respectively, which induce distinct EMT programs. Ye et al. (2015) cautioned that seemingly similar stem cell programs operating in tumor initiating cells and normal stem cells of the corresponding normal tissue are likely to differ significantly in their details.
Reclassified Variants
The homozygous deletion in the SNAI2 gene (602150.0001) identified in 2 patients with Waardenburg syndrome type 2 (WS2; see 193510) by Sanchez-Martin et al. (2002) has been reclassified as a variant of unknown significance. In 2 of 38 unrelated patients with WS2 and no mutation in the MITF gene (156845), Sanchez-Martin et al. (2002) detected a homozygous deletion of the SNAI2 gene (602150.0001).
The heterozygous deletion in the SNAI2 gene (172800.0002) identified in 3 patients with piebaldism (172800) by Sanchez-Martin et al. (2002) has been reclassified as a variant of unknown significance. In 3 of 17 unrelated patients with piebaldism in whom no mutations in the KIT protooncogene (164920) were detected, Sanchez-Martin et al. (2003) identified a heterozygous deletion of the SNAI2 gene (602150.0002).
Associations Pending Confirmation
In a Chinese girl with a severe form of ectodermal dysplasia (XHED; 305100) and piebaldism, Yang et al. (2014) identified a heterozygous mutation (Y304C) in the EDA1 gene (300451) and a 2-bp substitution (GC-AT) in the 5-prime UTR of the SNAI2 gene. The authors suggested that the EDA1 mutation was responsible for ectodermal dysplasia and the SNAI2 mutation was responsible for piebaldism.
Perez-Mancera et al. (2007) stated that Slug-null mice have a white forehead blaze, patchy depigmentation of the ventral body, tail, and feet, macrocytic anemia, and infertility. They found that Slug -/- mice also exhibited a marked deficiency in white adipose tissue (WAT) mass. In contrast, Slug-overexpressing mice showed an increase in WAT mass. Mouse embryonic fibroblasts (MEFs) and mouse 3T3L1 preadipocytes expressed high levels of Slug prior to differentiation, and expression decreased during hormone-stimulated differentiation. Slug deficiency in MEFs reduced their capacity to differentiate into adipocytes. Chromatin immunoprecipitation analysis showed that Slug expression in adipose tissue was associated with recruitment of histone deacetylase (see HDAC1; 601241) to the promoter region of Ppar-gamma-2 (601487), a transcription factor involved in adipocyte differentiation.
The mammalian core Hippo signaling components include Ste20 family kinases Mst1 (604965) and Mst2 (605030), which are homologous to Drosophila Hippo. To determine whether Hippo signaling controls mammalian heart size, Heallen et al. (2011) inactivated Hippo pathway components (e.g., SAV, 607203) in the developing mouse heart. Hippo-deficient embryos had overgrown hearts with elevated cardiomyocyte proliferation. Gene expression profiling and chromatin immunoprecipitation revealed that Hippo signaling negatively regulates a subset of Wnt (see 606359) target genes. Genetic interaction studies indicated that beta-catenin (116806) heterozygosity suppressed the Hippo cardiomyocyte overgrowth phenotype. Furthermore, the Hippo effector Yap (606608) interacts with beta-catenin on Sox2 (184429) and Snai2 genes. Heallen et al. (2011) concluded that their data uncovered a nuclear interaction between Hippo and Wnt signaling that restricts cardiomyocyte proliferation and controls heart size.
This variant, formerly titled WAARDENBURG SYNDROME, TYPE 2D, based on the report of Sanchez-Martin et al. (2002), has been reclassified based on the report of Mirhadi et al. (2020).
In 2 of 38 unrelated patients with Waardenburg syndrome (W2; see 193510) and no mutation in the MITF gene, Sanchez-Martin et al. (2002) detected homozygous deletions spanning the entire coding region of the SNAI2 gene. One patient (patient B), a 15-year-old girl born of nonconsanguineous, unaffected parents of Bangladeshi origin, had 4 unaffected sibs. The other patient (patient D) was a 3-year-old boy of nonconsanguineous, unaffected Dutch parents.
Mirhadi et al. (2020) called into the question the findings of Sanchez-Martin et al. (2002) and suggested that the findings may have been a result of a technical artifact. They cited the unpublished observation of a child with a heterozygous 1.7-Mb 8q11.1q11.21 deletion that included the entire SNAI2 gene whose clinical phenotype did not include pigmentation anomalies, deafness, or dysmorphia that would be suggestive of either Waardenburg syndrome or piebaldism.
This variant, formerly titled PIEBALDISM, based on the report of Sanchez-Martin et al. (2002), has been reclassified based on the report of Mirhadi et al. (2020).
In 3 individuals (patients A, B, and E) with piebaldism (172800), Sanchez-Martin et al. (2003) identified heterozygous deletions with similar breakpoints in the coding region of SNAI2 gene. Two of the patients had sporadic cases and the third patient had 2 affected sibs and an affected daughter; all parents were nonconsanguineous and unaffected. The authors stated that no mutations in the KIT protooncogene (164920) had been detected in these patients; however, Mirhadi et al. (2020) stated that one of these patients was later found to have a heterozygous mutation in the KIT gene (c.2665A-G, M889V, NM_000222). To their knowledge, the other 2 patients had not been retested.
Mirhadi et al. (2020) called into the question the findings of Sanchez-Martin et al. (2002) and suggested that the findings may have been a result of a technical artifact. They cited the unpublished observation of a child with a heterozygous 1.7-Mb 8q11.1q11.21 deletion that included the entire SNAI2 gene whose clinical phenotype did not include pigmentation anomalies, deafness, or dysmorphia that would be suggestive of either Waardenburg syndrome or piebaldism.
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Gupta, P. B., Kuperwasser, C., Brunet, J.-P., Ramaswamy, S., Kuo, W.-L., Gray, J. W., Naber, S. P., Weinberg, R. A. The melanocyte differentiation program predisposes to metastasis after neoplastic transformation. Nature Genet. 37: 1047-1054, 2005. [PubMed: 16142232] [Full Text: https://doi.org/10.1038/ng1634]
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Inukai, T., Inoue, A., Kurosawa, H., Goi, K., Shinjyo, T., Ozawa, K., Mao, M., Inaba, T., Look, A. T. SLUG, a ces-1-related zinc finger transcription factor gene with antiapoptotic activity, is a downstream target of the E2A-HLF oncoprotein. Molec. Cell 4: 343-352, 1999. [PubMed: 10518215] [Full Text: https://doi.org/10.1016/s1097-2765(00)80336-6]
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Perez-Losada, J., Sanchez-Martin, M., Rodriguez-Garcia, A., Flores, T., Sanchez, M. L., Orfao, A., Sanchez-Garcia, I. The zinc-finger transcription factor SLUG contributes to the function of the SCF-c-kit signaling pathway. Blood 100: 1274-1286, 2002. [PubMed: 12149208]
Perez-Mancera, P. A., Bermejo-Rodriguez, C., Gonzalez-Herrero, I., Herranz, M., Flores, T., Jimenez, R., Sanchez-Garcia, I. Adipose tissue mass is modulated by SLUG (SNAI2). Hum. Molec. Genet. 16: 2972-2986, 2007. [PubMed: 17905753] [Full Text: https://doi.org/10.1093/hmg/ddm278]
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Sanchez-Martin, M., Perez-Losada, J., Rodriguez-Garcia, A., Gonzalez-Sanchez, B., Korf, B. R., Kuster, W., Moss, C., Spritz, R. A., Sanchez-Garcia, I. Deletion of the SLUG (SNAI2) gene results in human piebaldism. Am. J. Med. Genet. 122A: 125-132, 2003. [PubMed: 12955764] [Full Text: https://doi.org/10.1002/ajmg.a.20345]
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Savagner, P., Yamada, K. M., Thiery, J. P. The zinc-finger protein Slug causes desmosome dissociation, an initial and necessary step for growth factor-induced epithelial-mesenchymal transition. J. Cell Biol. 137: 1403-1419, 1997. [PubMed: 9182671] [Full Text: https://doi.org/10.1083/jcb.137.6.1403]
Wu, W.-S., Heinrichs, S., Xu, D., Garrison, S. P., Zambetti, G. P., Adams, J. M., Look, A. T. Slug antagonizes p53-mediated apoptosis of hematopoietic progenitors by repressing puma. Cell 123: 641-653, 2005. [PubMed: 16286009] [Full Text: https://doi.org/10.1016/j.cell.2005.09.029]
Yang, Y., Zhao, R., He, X., Li, L., Chen, W., Wang, K., Zhao, L., Tu, M., Tang, J., Xie, Z., Zhu, Y. SNAI2 mutation causes human piebaldism. (Letter) Am. J. Med. Genet. 164A: 855-857, 2014. [PubMed: 24443330] [Full Text: https://doi.org/10.1002/ajmg.a.36332]
Ye, X., Tam, W. L., Shibue, T., Kaygusuz, Y., Reinhardt, F., Ng Eaton, E., Weinberg, R. A. Distinct EMT programs control normal mammary stem cells and tumour-initiating cells. Nature 525: 256-260, 2015. [PubMed: 26331542] [Full Text: https://doi.org/10.1038/nature14897]