Alternative titles; symbols
HGNC Approved Gene Symbol: ZNF423
Cytogenetic location: 16q12.1 Genomic coordinates (GRCh38): 16:49,487,524-49,859,279 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16q12.1 | Joubert syndrome 19 | 614844 | Autosomal dominant; Autosomal recessive | 3 |
| Nephronophthisis 14 | 614844 | Autosomal dominant; Autosomal recessive | 3 |
ZNF423 localizes to the ciliary transition zone and is also involved in DNA damage repair (Chaki et al., 2012).
By sequencing clones obtained from a size-fractionated brain cDNA library, Nagase et al. (1998) cloned ZNF423, which they designated KIAA0760. The deduced 1,206-amino acid protein shares significant similarity with rat Olf1/Ebf-associated zinc finger protein. RT-PCR ELISA detected high expression in brain, lung, skeletal muscle, and ovary, and intermediate expression in heart, liver, kidney, pancreas, spleen, and testis.
Hata et al. (2000) identified a 30-zinc finger protein, which they called OAZ, as a DNA-binding factor that associates with SMADs (see 601595) in response to bone morphogenetic protein-2 (BMP2; 112261), forming a complex that transcriptionally activates the homeobox regulator of Xenopus mesoderm and neural development, Xvent-2. Human OAZ is predicted to be a 1,224-amino acid protein containing a BMP-signaling module formed by 2 clusters of fingers that bind SMADs and the Xvent-2 BMP response element, respectively. Previously implicated as a transcriptional partner of OLF1/EBF in olfactory epithelium and lymphocyte development in the rat (Tsai and Reed, 1997), OAZ fulfills this role in transcription through clusters of fingers that are separate from the BMP-signaling module. Hata et al. (2000) showed that OAZ is a nuclear protein. In adult human tissues, Northern blot analysis detected a 7.5-kb OAZ transcript in brain, lung, skeletal muscle, heart, pancreas, and kidney, but not liver or placenta. A 5.5-kb OAZ transcript was also detected in heart and skeletal muscle. Analysis of additional human tissues revealed OAZ expression in aorta, ovary, pituitary, small intestine, fetal brain, fetal kidney, and adult brain, specifically in the substantia nigra, medulla, amygdala, thalamus, and cerebellum. Hata et al. (2000) suggested that the mutually exclusive use of OAZ by the BMP-SMAD and OLF pathways illustrates the dual role of a multizinc finger protein in signal transduction during development.
By radiation hybrid analysis, Nagase et al. (1998) mapped the ZNF423 gene to chromosome 16. Alcaraz et al. (2006) stated that the mouse Zfp423 gene maps to chromosome 8.
Gupta et al. (2010) identified the zinc finger protein Zfp423 as a factor enriched in preadipose versus nonpreadipose fibroblasts. Ectopic expression of Zfp423 in nonadipogenic NIH 3T3 fibroblasts robustly activates expression of Ppar-gamma (PPARG; 601487) in undifferentiated cells and permits cells to undergo adipocyte differentiation under permissive conditions. Short hairpin RNA-mediated reduction of Zfp423 expression in 3T3-L1 cells blunted preadipocyte Pparg expression and diminished the ability of those cells to differentiate. Furthermore, both brown and white adipocyte differentiation was markedly impaired in Zfp423-deficient mouse embryos. Zfp423 regulates Pparg expression, in part, through amplification of the BMP signaling pathway, an effect dependent on the SMAD-binding capacity of Zfp423. Gupta et al. (2010) concluded that their study identified Zfp423 as a transcriptional regulator of preadipocyte determination.
Using yeast 2-hybrid analysis, Chaki et al. (2012) showed that human ZNF423 interacted directly with CEP290 (610142), which localizes to the ciliary transition zone. ZNF423 colocalized with the DNA damage response proteins TIP60 (KAT5; 601409), SC35 (SRSF2; 600813), and CEP164 (614848) and with NPHP10 (SDCCAG8; 613524) at nuclear foci in immortalized human retinal pigment epithelial cells. Knockdown of Znf423 in mouse P19 cells resulted in increased radiation sensitivity compared with control cells. These findings indicated that ZNF423 plays a role in DNA damage response signaling and suggested that defects in DNA damage response may play a role in nephronophthisis-related ciliopathies.
Zhang et al. (2015) observed rapid proliferation of preadipocytes and expansion of the dermal fat layer after infection of the skin by Staphylococcus aureus. Impaired adipogenesis resulted in increased infection as seen in Zfp423(nur12) mice or in mice given inhibitors of Pparg. This host defense function was mediated through the production of Camp (600474) from adipocytes, since cathelicidin expression was decreased by inhibition of adipogenesis and adipocytes from Camp-null mice lost the capacity to inhibit bacterial growth. Zhang et al. (2015) concluded that the production of an antimicrobial peptide by adipocytes is an important element for protection against S. aureus infection of the skin.
By homozygosity mapping and whole-exome sequencing of 2 Turkish sibs with nephronophthisis-14 (NPHP14; 614844) manifest as infantile-onset kidney disease, cerebellar vermis hypoplasia, and situs inversus, Chaki et al. (2012) identified a homozygous mutation in the ZNF423 gene (P913L; 604557.0001). The mutation was predicted to result in a loss of function. Two of 96 additional patients with Joubert syndrome (JBTS19; see 614844) were found to carry heterozygous ZNF423 mutations (604557.0002 and 604557.0003). The heterozygous mutations caused a dominant-negative effect on protein function in cellular studies. Chaki et al. (2012) suggested that loss of function of proteins that have a dual role in centrosome and DNA repair signaling could cause a disturbance of cell-cycle checkpoint controls, which is detrimental to progenitor cell survival both during embryogenesis and later during tissue maintenance.
The nur12 mouse, which was identified in a large chemical mutagenesis screen, has an ataxic gait and cerebellar hypoplasia, including agenesis of the vermis. By positional cloning, Alcaraz et al. (2006) determined that nur12 is caused by a nonsense mutation in exon 4 of the mouse Zfp423 gene, resulting in loss of the corpus callosum, reduction of hippocampus, and a malformation of the cerebellum reminiscent of patients with Dandy-Walker syndrome (220200). Within the cerebellum, Zfp423 was expressed in both ventricular and external germinal zones. Loss of Zfp423 resulted in diminished proliferation by granule cell precursors in the external germinal layer, especially near the midline, and abnormal differentiation and migration of ventricular zone-derived neurons and Bergmann glia. Alcaraz et al. (2006) concluded that ZNF423 is required for patterning the development of neuronal and glial precursors in the developing brain, particularly in midline structures.
Cheng and Reed (2007) found that Znf423 -/- mice exhibited profound cerebellar defects and died by about 4 weeks. In the developing olfactory epithelium, Znf423 was expressed in newly differentiating olfactory receptor neurons, and knockout of Znf423 reduced the number of mature olfactory neurons due to elevated apoptosis and impaired axonal projections to the olfactory bulb. In mice with sustained Znf423 overexpression, they found arrested olfactory neuron maturation and perturbed immature and mature olfactory neuron gene expression patterns. Cheng and Reed (2007) concluded that ZNF423 participates in a developmental switch that regulates the transition from differentiation to maturation in olfactory neurons.
In 2 Turkish sibs, born of consanguineous parents, with nephronophthisis-14 (NPHP14; 614844) manifest as infantile-onset kidney disease, cerebellar vermis hypoplasia, and situs inversus, Chaki et al. (2012) identified a homozygous 2738C-T transition in exon 5 of the ZNF423 gene, resulting in a pro913-to-leu (P913L) substitution in a highly conserved residue between zinc fingers 21 and 22, likely resulting in loss of function. The mutation was found by homozygosity mapping combined with whole-exome sequencing, and was not found in more than 270 controls or in the exome variant server database. Chaki et al. (2012) referred to these patients as having an NPHP-related ciliopathy, despite the presence of cerebellar vermis hypoplasia.
In an Icelandic patient with Joubert syndrome-19 (JBTS19; see 614844) manifest as polycystic kidney disease, Leber congenital amaurosis, and cerebellar vermis hypoplasia, Chaki et al. (2012) identified a heterozygous 1-bp deletion (1518delC) in exon 5 of the ZNF423 gene, resulting in a frameshift, premature termination (Pro506fsTer43), and the removal of several zinc fingers important for interactions with other factors. The patient had no sibs and parental DNA was not available for study. The mutation was not found in more than 270 controls or in the exome variant server database. In vitro cellular expression studies showed that the mutation reduced the mitotic index and yielded a dominant-negative effect. The truncation also abrogated the interaction of ZNF423 with PARP1 (173870).
In a patient with JBTS19 (see 614844) manifest as polycystic kidney disease, retinal degeneration, cerebellar vermis hypoplasia, and perinatal breathing abnormality, Chaki et al. (2012) identified a heterozygous 3829C-T transition in exon 9 of the ZNF423 gene, resulting in a his1277-to-tyr (H1277Y) substitution at a highly conserved residue in the terminal zinc finger domain important for interaction with other factors. The patient had no sibs and parental DNA was not available for study. The mutation was not found in more than 270 controls or in the exome variant server database. In vitro cellular expression studies showed that the H1277Y mutation reduced the mitotic index and yielded a dominant-negative effect. The mutation also inhibited multimerization of ZNF423.
Alcaraz, W. A., Gold, D. A., Raponi, E., Gent, P. M., Concepcion, D., Hamilton, B. A. Zfp423 controls proliferation and differentiation of neural precursors in cerebellar vermis formation. Proc. Nat. Acad. Sci. 103: 19424-19429, 2006. [PubMed: 17151198] [Full Text: https://doi.org/10.1073/pnas.0609184103]
Chaki, M., Airik, R., Ghosh, A. K., Giles, R. H., Chen, R., Slaats, G. G., Wang, H., Hurd, T. W., Zhou, W., Cluckey, A., Gee, H. Y., Ramaswami, G., and 61 others. Exome capture reveals ZNF423 and CEP164 mutations, linking renal ciliopathies to DNA damage response signaling. Cell 150: 533-548, 2012. [PubMed: 22863007] [Full Text: https://doi.org/10.1016/j.cell.2012.06.028]
Cheng, L. E., Reed, R. R. Zfp423/OAZ participates in a developmental switch during olfactory neurogenesis. Neuron 54: 547-557, 2007. [PubMed: 17521568] [Full Text: https://doi.org/10.1016/j.neuron.2007.04.029]
Gupta, R. K., Arany, Z., Seale, P., Mepani, R. J., Ye, L., Conroe, H. M., Roby, Y. A., Kulaga, H., Reed, R. R., Spiegelman, B. M. Transcriptional control of preadipocyte determination by Zfp423. Nature 464: 619-623, 2010. [PubMed: 20200519] [Full Text: https://doi.org/10.1038/nature08816]
Hata, A., Seoane, J., Lagna, G., Montalvo, E., Hemmati-Brivanlou, A., Massague, J. OAZ uses distinct DNA- and protein-binding zinc fingers in separate BMP-Smad and Olf signaling pathways. Cell 100: 229-240, 2000. [PubMed: 10660046] [Full Text: https://doi.org/10.1016/s0092-8674(00)81561-5]
Nagase, T., Ishikawa, K., Suyama, M., Kikuno, R., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. XI. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 5: 277-286, 1998. [PubMed: 9872452] [Full Text: https://doi.org/10.1093/dnares/5.5.277]
Tsai, R. Y. L., Reed, R. R. Cloning and functional characterization of Roaz, a zinc finger protein that interacts with O/E-1 to regulate gene expression: implications for olfactory neuronal development. J. Neurosci. 17: 4159-4169, 1997. [PubMed: 9151733] [Full Text: https://doi.org/10.1523/JNEUROSCI.17-11-04159.1997]
Zhang, L., Guerrero-Juarez, C. F., Hata, T., Bapat, S. P., Ramos, R., Plikus, M. V., Gallo, R. L. Dermal adipocytes protect against invasive Staphylococcus aureus skin infection. Science 347: 67-71, 2015. [PubMed: 25554785] [Full Text: https://doi.org/10.1126/science.1260972]