Alternative titles; symbols
HGNC Approved Gene Symbol: DACH1
Cytogenetic location: 13q21.33 Genomic coordinates (GRCh38) : 13:71,437,966-71,867,204 (from NCBI)
DACH1 a transcriptional repressor that is involved in cell fate determination during development (Cao et al., 2021)
The Drosophila 'dachshund' (dac) gene is involved in both eye and leg development. Dac, 'eyeless' (ey), and 'eyes absent' (eya) are considered potential master genes in eye formation. By searching an EST database, Hammond et al. (1998) identified cDNAs corresponding to DACH, a human dac homolog. The authors used DACH cDNAs as a probe to isolate mouse Dach cDNAs from an embryonic library. Both mouse and human Dach mRNAs contain long stretches of trinucleotide repeats in their 5-prime untranslated regions. The predicted 517-amino acid human DACH protein is 99% identical to Dach. Sequence analysis revealed that Drosophila dac and mammalian DACH proteins share conserved domains at their N and C termini, designated Dachbox-N and Dachbox-C, respectively. The SKI (164780) protooncogene and the related SNO (165340) protein also contain Dachbox-N, as well as a C-terminal motif corresponding to the helical coiled-coil domain beginning in Dachbox-C. While the C-terminal motif is only weakly conserved between SKI and SNO and the dac-related proteins at the level of sequence, it is likely to be highly homologous at the level of tertiary structure and may mediate protein dimerization. Hammond et al. (1998) considered SKI, SNO, and the dac-related proteins to be members of a gene superfamily. In situ hybridization revealed that mouse Dach mRNA is expressed in eye, limb, rib primordia, central nervous system, and genital eminence in embryos. Pax6 (607108), the mammalian homolog of ey, and Dach show overlapping but nonidentical expression patterns. However, Dach expression in forebrain is unaffected in Pax6 mutant (small eye) mice, indicating that, at least in brain, Pax6 does not directly regulate Dach. The authors concluded that Dach joins a group of homologous eye genes shared by Drosophila and mouse, supporting the concept that a conserved genetic network operates in eye development in diverse organisms.
Ayres et al. (2001) reported that DACH encodes a 706-amino acid protein with an observed molecular weight of 97 kD.
Using Northern blot analysis, Ayres et al. (2001) detected a predominant 5.2-kb DACH transcript expressed most abundantly in adult kidney, heart, liver, skeletal muscle, and placenta, with lower expression in brain, spleen, lung, and peripheral leukocytes. Using RT-PCR, Ayres et al. (2001) detected 3 minor splice variants of DACH. Using immunohistochemistry, Ayres et al. (2001) characterized the expression of the mouse DACH1 protein in specific cell types within the developing kidneys, eyes, cochleae, and limb buds.
Using confocal microscopy in human TERT-RPE1 cells, Umair et al. (2021) observed that DACH1 localized with the basal body marker EB3 (605788) at the base of the cilia.
Ayres et al. (2001) determined that the DACH gene contains 12 exons and spans 400 kb.
Based on sequence similarity to STS WI-18453 (G24265) and by fluorescence in situ hybridization, Hammond et al. (1999) mapped the DACH gene to 13q22. Using fluorescence in situ hybridization, these authors mapped the mouse Dach gene to chromosome 14, band E3, in a region showing homology of synteny to human 13q22.
In mice homozygously deleted for the Six6 (606326) homeodomain factor, Li et al. (2002) observed that Six6, in association with Dach corepressors, regulates early progenitor cell proliferation during mammalian retinogenesis and pituitary development by directly repressing cyclin-dependent kinase inhibitors, including the p27Kip1 (600778) promoter. Li et al. (2002) concluded that their data revealed a molecular mechanism by which a tissue-specific transcriptional repressor-corepressor complex can provide an organ-specific strategy for physiologic expansion of precursor populations.
Wu et al. (2008) noted that loss of DACH1 is associated with poor prognosis in invasive breast cancer. They showed that DACH1 induction inhibited migration of human breast cancer cell lines and oncogene-transformed human breast epithelial cell lines. The inhibitory effect required the Dac and Ski/Sno domain of DACH1. Proteomic analysis and neutralization assays identified IL8 (146930) as a critical target of DACH1. Chromatin immunoprecipitation analysis revealed that DACH1 bound the IL8 promoter and repressed it through AP1 (165160)- and NFKB (see 164011)-binding sites. Wu et al. (2008) concluded that DACH1 is part of a pathway by which an endogenous cell-fate determination factor blocks oncogene-dependent tumor metastasis.
Using short interfering RNA, Umair et al. (2021) depleted DACH1 in human TERT-RPE1 cells and observed a reduction of DACH1 signal at the base of cilia as well as reduced ciliation and reduced cilia length. The authors concluded that DACH1 plays a role in ciliogenesis.
Cao et al. (2021) found that mouse Dach1 mutations that converted injury-resistant podocytes into injury-susceptible podocytes resulted in decreased Dach1 expression. Likewise, database analysis showed diminished podocyte DACH1 expression levels in patients with diabetic kidney disease (DKD), and these reduced expression levels correlated strongly with poor clinical outcomes.
In a transcriptomewide association study, Doke et al. (2021) identified DACH1 as a kidney disease risk gene. Genetic variants associated with kidney function localized to DACH1 regulatory regions in the distal part of the kidney tubule segment. In corroboration, immunofluorescence staining revealed that DACH1 was expressed in podocytes and in distal tubule cells in mouse and human.
Associations Pending Confirmation
In a patient with renal dysplasia, Schild et al. (2013) identified homozygosity for missense mutations in 2 genes: an R684C substitution in DACH1, and an N150K substitution in BMP4 (112262). At 4 years of age, the proband had anemia and renal insufficiency, and ultrasound revealed bilateral multiple cysts and hyperechogenic parenchyma. His kidney function deteriorated and he had end-stage renal disease by age 5. He underwent allogenic kidney graft 7 months later, and at age 19 continued to have good graft function. His parents were double cousins, and each carried both mutations in heterozygosity. Family history showed that his father had bilateral medullary renal cysts without impairment of renal function, and a second cousin had died shortly after birth from undefined renal cystic disease. The proband was the only family member homozygous for both mutations; however, an unaffected sister was homozygous for N150K in BMP4 and an unaffected maternal uncle was homozygous for R684C in DACH1. Both of these relatives had normal renal ultrasound and normal kidney function. Studies in transfected cells showed enhanced repression of TGF-beta (TGFB1; 190180) signaling with the DACH1 mutant compared to wildtype protein. The authors noted that the N150K substitution in BMP4 previously had been reported in homozygosity in a patient with renal dysplasia (Weber et al., 2008).
For discussion of a possible association between postaxial polydactyly type A (see 602085) and mutation in the DACH1 gene, see 603803.0001.
Davis et al. (2001) generated Dach1-deficient mice which died during postnatal day 1 and exhibited failure to suckle, cyanosis, and respiratory distress. The authors hypothesized that a lack of morphologic defects in these mutant mice may be due to compensation by an additional Dach homolog.
Li et al. (2003) reported that Six1 (601205) is required for the development of murine kidney, muscle, and inner ear and that it exhibits synergistic genetic interactions with Eya (601653) factors. Li et al. (2003) demonstrated that the Eya family has a protein phosphatase function, and that its enzymatic activity is required for regulating genes encoding growth control and signaling molecules, modulating precursor cell proliferation. The phosphatase function of Eya switches the function of Six1-Dach from repression to activation, causing transcriptional activation through recruitment of coactivators. The gene-specific recruitment of a coactivator with intrinsic phosphatase activity provides a molecular mechanism for activation of specific gene targets, including those regulating precursor cell proliferation and survival in mammalian organogenesis. Eya1 +/- Six1 +/- double heterozygous mice had a defect in kidney development, which was not observed in single heterozygotes for either gene deletion, suggesting that Six1 and Eya1 act in the same genetic pathway. Notably, there was a complete absence of all hypaxial muscle in Six1 -/- Eya1 -/- double knockout mice and severe reduction of epaxial muscle, a phenotype resembling that seen in mice homozygous for deletion of Myog (159980) and in double knockouts for MyoD (159970)/Myf5 (159990) and Pax3 (606597)/Myf5. Interestingly, although mutation of Six1 or Eya1 has minimal or no effect on pituitary development, mice with both genes deleted have a pituitary that is approximately 5- to 10-fold smaller by volume than the wildtype gland.
Cao et al. (2021) found that Dach1 -/- mice were born at the expected mendelian ratio and appeared grossly similar to wildtype, but they died prior to the second postnatal day, likely from kidney failure. Mice with podocyte-specific Dach1 knockout maintained normal glomerular architecture under basal conditions but developed severe podocyte injury with rapid progression to end-stage renal disease after onset of diabetes. In contrast, inducible podocyte-specific expression of Dach1 protected transgenic mice from diabetic glomerular injury and slowed DKD progression. RNA sequencing and database analysis revealed conversely overlapping glomerular transcriptomic signatures between podocyte-specific Dach1-knockout mice and Ptip (608254)-knockout mice, with upregulated genes possessing higher-than-expected numbers of promoter Dach1-binding sites. Ptip, an essential component of the activating histone H3 (see 602810) lys4 trimethylation (H3K4Me3) complex, interacted with Dach1 and was recruited by Dach1 to its promoter-binding sites, causing diminished H3K4Me3 levels to repress the transcription of DACH1 target genes in podocytes. Dach1 knockdown combined with hyperglycemia triggered Dach1 target gene derepression and increased promoter H3K4Me3 levels in mouse podocytes. Analysis with human podocytes indicated that DACH1-mediated transcriptional repression in podocytes required DACH1 sequence-specific DNA binding.
Doke et al. (2021) found that mice with tubule-specific heterozygous or homozygous deletion of Dach1 were born at the expected mendelian ratios and appeared healthy at birth, but they were more susceptible to kidney disease. In contrast, kidney tubule-specific transgenic expression of Dach1 protected mice from kidney fibrosis development. Single-cell expression analysis showed that mice heterozygous for tubule-specific Dach1 deletion had more cycling cells in their kidneys. Chromatin immunoprecipitation-sequencing data and RT-PCR analysis indicated that DACH1 functioned as a transcriptional repressor to control cell cycle genes and cell proliferation both in vireo and in vivo. Further analysis showed that Dach1 acted as a transcriptional repressor of myeloid chemotactic factors in mouse kidney tubule cells to control macrophage infiltration and kidney disease development. In corroboration, DACH1 expression was decreased and correlated with fibrosis, proliferation, and inflammation in kidneys of patients with chronic kidney disease.
This variant is classified as a variant of unknown significance because its contribution to type A postaxial polydactyly (see 602085) has not been confirmed.
In 2 brothers with type A postaxial polydactyly, Umair et al. (2021) identified homozygosity for a c.563G-A transition (c.563G-A, NM_080760.5) in exon 2 of the DACH1 gene, resulting in a cys188-to-tyr (C188W) substitution at a highly conserved residue. Their unaffected first-cousin parents and an unaffected brother were heterozygous for the variant, which was not present in an unaffected sister. The variant was found in the ExAC and gnomAD databases at very low minor allele frequency (MAFs of 2.523 x 10(-5) and 0.00002427, respectively), only in heterozygosity. The brothers had complete and well-developed extra digits on the ulnar side of the hands and laterally on the feet, as well as 2-3 partial syndactyly of the toes. Both affected individuals and their father had kidney stones, but exhibited no other features such as hearing loss, obesity, renal disease, or eye findings.
Ayres, J. A., Shum, L., Akarsu, A. N., Dashner, R., Takahashi, K., Ikura, T., Slavkin, H. C., Nuckolls, G. H. DACH: genomic characterization, evaluation as a candidate for postaxial polydactyly type A2, and developmental expression pattern of the mouse homologue. Genomics 77: 18-26, 2001. [PubMed: 11543628] [Full Text: https://doi.org/10.1006/geno.2001.6618]
Cao, A., Li, J., Asadi, M., Basgen, J. M., Zhu, B., Yi, Z., Jiang, S., Doke, T., El Shamy, O., Patel, N., Cravedi, P., Azeloglu, E. U., and 12 others. DACH1 protects podocytes from experimental diabetic injury and modulates PTIP-H3K4Me3 activity. J. Clin. Invest. 131: e141279, 2021. [PubMed: 33998601] [Full Text: https://doi.org/10.1172/JCI141279]
Davis, R. J., Shen, W., Sandler, Y. I., Amoui, M., Purcell, P., Maas, R., Ou, C.-N., Vogel, H., Beaudet, A. L., Mardon, G. Dach1 mutant mice bear no gross abnormalities in eye, limb, and brain development and exhibit postnatal lethality. Molec. Cell. Biol. 21: 1484-1490, 2001. [PubMed: 11238885] [Full Text: https://doi.org/10.1128/MCB.21.5.1484-1490.2001]
Doke, T., Huang, S., Qiu, C., Liu, H., Guan, Y., Hu, H., Ma, Z., Wu, J., Miao, Z., Sheng, X., Zhou, J., Cao, A., Li, J., Kaufman, L., Hung, A., Brown, C. D., Pestell, R., Susztak, K. Transcriptome-wide association analysis identifies DACH1 as a kidney disease risk gene that contributes to fibrosis. J. Clin. Invest. 131: e141801, 2021. [PubMed: 33998598] [Full Text: https://doi.org/10.1172/JCI141801]
Hammond, K. L., Hanson, I. M., Brown, A. G., Lettice, L. A., Hill, R. E. Mammalian and Drosophila dachshund genes are related to the Ski proto-oncogene and are expressed in eye and limb. Mech. Dev. 74: 121-131, 1998. [PubMed: 9651501] [Full Text: https://doi.org/10.1016/s0925-4773(98)00071-9]
Hammond, K. L., Lettice, L. A., Hill, R. E., Lee, M., Boyle, S., Hanson, I. M. Human (DACH) and mouse (Dach) homologues of Drosophila dachshund map to chromosomes 13q22 and 14E3, respectively. Genomics 55: 252-253, 1999. [PubMed: 9933575] [Full Text: https://doi.org/10.1006/geno.1998.5662]
Li, X., Ohgi, K. A., Zhang, J., Krones, A., Bush, K. T., Glass, C. K., Nigam, S. K., Aggarwal, A. K., Maas, R., Rose, D. W., Rosenfeld, M. G. Eya protein phosphatase activity regulates Six1-Dach-Eya transcriptional effects in mammalian organogenesis. Nature 426: 247-254, 2003. Note: Erratum: Nature 427: 265 only, 2004. [PubMed: 14628042] [Full Text: https://doi.org/10.1038/nature02083]
Li, X., Perissi, V., Liu, F., Rose, D. W., Rosenfeld, M. G. Tissue-specific regulation of retinal and pituitary precursor cell proliferation. Science 297: 1180-1183, 2002. [PubMed: 12130660] [Full Text: https://doi.org/10.1126/science.1073263]
Schild, R., Knuppel, T., Konrad, M., Bergmann, C., Trautmann, A., Kemper, M. J., Wu, K., Yaklichkin, S., Wang, J., Pestell, R., Muller-Wiefel, D. E., Schaefer, F., Weber, S. Double homozygous missense mutations in DACH1 and BMP4 in a patient with bilateral cystic renal dysplasia. Nephrol. Dial. Transplant. 28: 227-32, 2013. [PubMed: 23262432] [Full Text: https://doi.org/10.1093/ndt/gfs539]
Umair, M., Palander, O., Bilal, M., Almuzzaini, B., Alam, Q., Ahmad, F., Younus, M., Khan, A., Waqas, A., Rafeeq, M. M., Alfadhel, M. Biallelic variant in DACH1, encoding Dachshund Homolog 1, defines a novel candidate locus for recessive postaxial polydactyly type A. Genomics 113: 2495-2502, 2021. [PubMed: 34022343] [Full Text: https://doi.org/10.1016/j.ygeno.2021.05.015]
Weber, S., Taylor, J. C., Winyard, P., Baker, K. F., Sullivan-Brown, J., Schild, R., Knuppel, T., Zurowska, A. M., Caldas-Alfonso, A., Litwin, M., Emre, S., Ghiggeri, G. M., Bakkaloglu, A., Mehls, O., Antignac, C., Escape Network, Schaefer, F., Burdine, R. D. SIX2 and BMP4 mutations associate with anomalous kidney development. J. Am. Soc. Nephrol. 19: 891-903, 2008. [PubMed: 18305125] [Full Text: https://doi.org/10.1681/ASN.2006111282]
Wu, K., Katiyar, S., Li, A., Liu, M., Ju, X., Popov, V. M., Jiao, X., Lisanti, M. P., Casola, A., Pestell, R. G. Dachshund inhibits oncogene-induced breast cancer cellular migration and invasion through suppression of interleukin-8. Proc. Nat. Acad. Sci. 105: 6924-6929, 2008. [PubMed: 18467491] [Full Text: https://doi.org/10.1073/pnas.0802085105]