Alternative titles; symbols
HGNC Approved Gene Symbol: ZFHX3
Cytogenetic location: 16q22.2-q22.3 Genomic coordinates (GRCh38): 16:72,782,885-73,891,930 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16q22.2-q22.3 | {Atrial fibrillation 8, susceptibility to} | 613055 | Autosomal dominant | 3 |
| Prostate cancer, somatic | 176807 | 3 | ||
| Spinocerebellar ataxia 4 | 600223 | Autosomal dominant | 3 |
Tissue-specific expression of the human alpha-fetoprotein (AFP) gene (104150) is strongly stimulated by an enhancer present 3.3 to 4.9 kb upstream of the transcription initiation site. One of the enhancer elements contains an AT-rich core sequence (AT motif). To determine the nuclear factor in hepatoma cell lines that interacts with the human AFP enhancer AT motif, Morinaga et al. (1991) screened a hepatoma cDNA expression library with an AFP enhancer fragment that bore the AT motif. They succeeded in isolating a cDNA that can code for an AT motif-binding factor, which they termed ATBF1. This was the largest DNA-binding protein identified to that time and the first protein shown to contain multiple homeodomains and multiple zinc finger motifs. The protein had a predicted mass of 306 kD and contained 4 homeodomains and 17 zinc finger motifs.
Dong et al. (2010) stated that full-length human ATBF1 contains 3,703 amino acids and that it has an ATPase A motif, 2 DEAH box-like sequences, 4 homeodomains, and 23 zinc finger motifs.
By confocal imaging in adult wildtype mouse heart tissue, Jameson et al. (2023) demonstrated expression of Zfhx3 primarily in atria.
By fluorescence in situ hybridization, Yamada et al. (1995) mapped the ATBF1 gene to 16q22.3-q23.1. Yamada et al. (1996) used fluorescence in situ hybridization to assign the Atbf1 gene to mouse chromosome 8E1.
Qi et al. (2008) identified 3 highly conserved regulatory elements in the promoter region of the mouse Pit1 gene (POU1F1; 173110) and found that Atbf1 bound and activated Pit1 from 1 of these elements, EE-alpha. Pituitaries of mice with a hypomorphic Atbf1 allele showed decreased expression of the somatotrope marker, Gh (139250), and almost no expression of the thyrotrope marker, Tshb (188540). Qi et al. (2008) concluded that ATBF1 is required for early PIT1 transcriptional activation.
Dong et al. (2010) found that ATBF1 inhibited estrogen receptor (ER, or ESR1; 133430)-mediated gene transcription, cell growth, and proliferation in ER-positive breast cancer cell lines. In vitro and in vivo immunoprecipitation experiments revealed that ATBF1 interacted directly with ER, and mutation analysis identified multiple domains in both proteins that mediated the interaction. ATBF1 inhibited ER function by selectively competing with the steroid receptor coactivator AIB1 (NCOA3; 601937), but not GRIP1 (NCOA2; 601993) or SRC1 (NCOA1; 602691), for binding to ER.
Jameson et al. (2023) performed differential expression analysis as well as gene ontology and pathway enrichment analysis of left and right mouse atria from 6-month-old mice that were wildtype, heterozygous, or homozygous for ZFHX3 knockout. Their findings suggested that ZFHX3 plays a role in the regulation of gene signaling pathways involved in cardiac pathophysiology. To determine which genes in atrial cardiomyocytes are putatively regulated directly by ZFHX3, the authors analyzed human cardiac single-nucleus ATAC (assay for transposase-accessible chromatin)-sequencing data obtained from each of the 4 cardiac chambers. Among the top enriched terms for the putative ZFHX3 cistrome were cardiac conduction, heart contraction, and Ca(2+) transport. Extracting atrial-enriched data peaks and performing motif enrichment analysis for ZFHX3 identified 4,174 ZFHX3 atrial cardiomyocyte-specific binding sites, of which 306 genes were identified as differentially expressed. Gene ontology analysis of those 306 direct ZFHX3 target genes uncovered enrichment for genes with roles in cardiac development, VEGF (192240) signaling, Wnt (see 164820) signaling, calcium binding, and heart contraction. The directionality of expression was consistent with both positive and negative regulation by ZFHX3 in cardiomyocytes.
Atrial Fibrillation 8
Jameson et al. (2023) defined the atrial fibrillation-8 (ATFB8; 613055) locus using SNPs in strong linkage disequilibrium with an ATFB8-associated SNP (rs2106261) previously identified by Benjamin et al. (2009), located in an intron of the ZFHX3 gene. Jameson et al. (2023) obtained a 74-kb region containing 52 common variants with a minor allele frequency greater than 1% in individuals of European descent. Intersecting the 52 ATFB-associated SNPs on 16q22 with the DNaseI hypersensitivity signal in human cardiomyocytes identified 6 candidate SNPs that overlapped with active chromatin marks. The authors then assessed the effect of the 6 candidates on gene expression in human pluripotent stem cell-derived cardiomyocytes (PSC-CMs), and found only 1 SNP (C-A, rs12931021; 104155.0002) in the ZFHX3 gene that exhibited differential activity dependent on genotype. The authors concluded that ZFHX3 is the causal gene at the ATFB8 locus at 16q22, with rs12931021 being a functional SNP mediating the genetic association with increased risk of atrial fibrillation correlated to reduced ZFHX3 expression.
Spinocerebellar Ataxia 4
In 8 affected individuals from 5 Swedish families with autosomal dominant spinocerebellar ataxia-4 (SCA4; 600223), Wallenius et al. (2024) identified a heterozygous 3-bp (GGC) repeat expansion in the last coding exon (exon 10) of the ZFHX3 gene (104155.0003); the GGC repeat encoded a glycine residue. All families originated from Skane, the southernmost region of Sweden, and haplotype analysis indicated a founder effect. Two of the families had previously been reported (see Moller et al., 1978 and Wictorin et al., 2014). The repeat was expanded to greater than 40 repeats (range 42 to 74) in affected individuals, whereas the most common nonexpanded repeat length was reported as 21 repeats (range 14 to 26) in controls. The nonexpanded repeat in controls consisted of 20 glycine residues interrupted by a single serine. All nonexpanded alleles had interruptions within the GGC repeat; the interruptions were predominantly synonymous GGT and a nonsynonymous AGT (serine). Pathogenic expanded alleles did not contain interruptions: GGC was the only repeat unit. Genetic anticipation was observed, and there was a correlation between longer repeat expansions and earlier age at symptom onset.
Somatic Mutations
The long arm of chromosome 16 is frequently deleted in human cancers. Sun et al. (2005) presented evidence that the ATBF1 gene is a good candidate for the 16q22 tumor suppressor gene. They narrowed the region of deletion at 16q22 to 861 kb containing ATBF1. ATBF1 mRNA was abundant in normal prostates but more scarce in approximately half of prostate cancers tested. In 24 (36%) of 66 cancers examined, Sun et al. (2005) identified 22 unique somatic mutations (see, e.g., 104155.0001), many of which impaired ATBF1 function. Furthermore, ATBF1 inhibited cell proliferation. Sun et al. (2005) concluded that loss of ATBF1 is one mechanism that defines the absence of growth control in prostate cancer.
Jameson et al. (2023) generated mice that were heterozygous or homozygous for cardiomyocyte-restricted loss of Zfhx3, and observed a high incidence of premature death in the mutant mice, at age 10 months in the knockout mice and 12 months in the heterozygotes, compared to wildtype littermates. Cardiac MRI at age 3 months showed a significantly reduced ejection fraction and significantly increased left atrial size in the knockout mice compared to controls. By 9 to 11 months of age, Zfhx3 knockout mice displayed massively dilated hearts with large thrombi in both the left and right atria and significantly increased fibrosis of the atrial wall and left ventricle. In addition, the mutant mice exhibited a premorbid phenotype indicating advanced heart failure, including diffuse edema/anasarca, abdominal distention presumably due to ascites, tachypnea, and muscle wasting. In vivo cardiac electrophysiology testing at age 3 months demonstrated a gene-dose response in inducible atrial arrhythmias by programmed stimulation in the mice, with the knockout mice having a higher incidence of atrial arrhythmias/atrial fibrillation than heterozygotes or wildtype mice. The knockout mice were also more prone to arrhythmia induction and showed an increased frequency of atrial arrhythmias. Ex vivo optical mapping in knockout mouse hearts demonstrated significantly slower right atrial conduction, and knockout left atrial cardiomyocytes showed abnormal calcium handling compared to wildtype. The authors concluded that loss of Zfhx3 causes conditions that predispose to increased automaticity, resulting in the observed increased susceptibility to atrial arrhythmias/atrial fibrillation.
In 4 cases of low- to midgrade primary prostate cancer (176807), Sun et al. (2005) identified a 24-bp deletion in exon 10 of the ATBF1 gene, 10814del24, resulting in loss of 8 amino acids, beginning with codon 3381, in a glutamine-rich domain. The deletion was also identified in a microdissected high-grade primary metastasis.
Among 6 candidate SNPs within the atrial fibrillation-associated locus on chromosome 16q22 (ATFB8; 613055), Jameson et al. (2023) identified only 1 SNP, a C-to-A transversion in the ZFHX3 gene (rs12931021C-A), that exhibited differential activity dependent on genotype, with the nonrisk C allele being 3.9-fold more active than the risk-associated A allele. Chromatin immunoprecipitation analysis in pluripotent stem cell-derived cardiomyocytes (PSC-CMs) confirmed the genotype-dependent regulatory activity at rs12931021. Using CRISPR-Cas9 to delete a 219-bp region harboring rs12931021 in PSC-CMs, the authors observed that the deleted cells expressed a significantly lower level of ZFHX3 than wildtype cells. In addition, analysis of isogenic PSC-CMs demonstrated a dose relationship between nonrisk C allele number and greater ZFHX3 expression. The authors concluded that rs12931021 is a functional SNP mediating the genetic association with increased risk of atrial fibrillation correlated to reduced ZFHX3 expression.
In 8 affected individuals from 5 Swedish families with autosomal dominant spinocerebellar ataxia-4 (SCA4; 600223), Wallenius et al. (2024) identified a heterozygous 3-bp (GGC) repeat expansion in the last coding exon (exon 10) of the ZFHX3 gene; the GGC repeat encoded a glycine residue. All families originated from Skane, the southernmost region of Sweden, and haplotype analysis indicated a founder effect. Two of the families had previously been reported (see Moller et al., 1978 and Wictorin et al., 2014). The repeat was expanded to greater than 40 repeats (range 42 to 74) in affected individuals, whereas the most common nonexpanded repeat length was reported as 21 repeats (range 14 to 26) in controls. The nonexpanded repeat in controls consisted of 20 glycine residues interrupted by a single serine. All nonexpanded alleles had interruptions within the GGC repeat; the interruptions were predominantly synonymous GGT and a nonsynonymous AGT (serine). Pathogenic expanded alleles did not contain interruptions: GGC was the only repeat unit. Genetic anticipation was observed, and there was a correlation between longer repeat expansions and earlier age at symptom onset. Long-read sequencing in a patient from family 1 who had onset at age 37 years showed 57 uninterrupted GGC repeats, whereas a patient in a later generation in family 1 who had onset at 15 years of age had 74 uninterrupted GGC repeats. Functional studies of the variant and studies of patient cells were not performed. However, postmortem examination of a patient who died at 28 years of age showed mild cerebellar atrophy with neuronal loss and gliosis, a loss of pigmented cells in the substantia nigra, and moderate cell loss in the locus ceruleus. Nerve cells of the myenteric plexus in the esophagus contained p62 (SQSTM1; 601530)-immunoreactive inclusions. Alpha-synuclein (SNCA; 163890) immunoreactivity was seen in brainstem and medulla oblongata neurons, in the hippocampus, and in myenteric ganglion cells in the gastrointestinal tract. Lewy bodies were not observed.
Benjamin, E. J., Rice, K. M., Arking, D. E., Pfeufer, A., van Noord, C., Smith, A. V., Schnabel, R. B., Bis, J. C., Boerwinkle, E., Sinner, M. F., Dehghan, A., Lubitz, S. A., and 44 others. Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry. Nature Genet. 41: 879-881, 2009. [PubMed: 19597492] [Full Text: https://doi.org/10.1038/ng.416]
Dong, X.-Y., Sun, X., Guo, P., Li, Q., Sasahara, M., Ishii, Y., Dong, J.-T. ATBF1 inhibits estrogen receptor (ER) function by selectively competing with AIB1 for binding to the ER in ER-positive breast cancer cells. J. Biol. Chem. 285: 32801-32809, 2010. [PubMed: 20720010] [Full Text: https://doi.org/10.1074/jbc.M110.128330]
Jameson, H. S., Hanley, A., Hill, M. C., Xiao, L., Ye, J., Bapat, A., Ronzier, E., Hall, A. W., Hucker, W. J., Clauss, S., Barazza, M., Silber, E., Mina, J. A., Tucker, N. R., Mills, R. W., Dong, J.-T., Milan, D. J., Ellinor, P. T. Loss of the atrial fibrillation-related gene, Zfhx3, results in atrial dilation and arrhythmias. Circ. Res. 133: 313-329, 2023. [PubMed: 37449401] [Full Text: https://doi.org/10.1161/CIRCRESAHA.123.323029]
Moller, E., Hindfelt, B., Olsson, J. E. HLA-determination in families with hereditary ataxia. Tissue Antigens 12: 357-366, 1978. [PubMed: 85351] [Full Text: https://doi.org/10.1111/j.1399-0039.1978.tb01345.x]
Morinaga, T., Yasuda, H., Hashimoto, T., Higashio, K., Tamaoki, T. A human alpha-fetoprotein enhancer-binding protein, ATBF1, contains four homeodomains and seventeen zinc fingers. Molec. Cell. Biol. 11: 6041-6049, 1991. [PubMed: 1719379] [Full Text: https://doi.org/10.1128/mcb.11.12.6041-6049.1991]
Qi, Y., Ranish, J. A., Zhu, X., Krones, A., Zhang, J., Aebersold, R., Rose, D. W., Rosenfeld, M. G., Carriere, C. Atbf1 is required for the Pit1 gene early activation. Proc. Nat. Acad. Sci. 105: 2481-2486, 2008. [PubMed: 18272476] [Full Text: https://doi.org/10.1073/pnas.0712196105]
Sun, X., Frierson, H. F., Chen, C., Li, C., Ran, Q., Otto, K. B., Cantarel, B. L., Vessella, R. L., Gao, A. C., Petros, J., Miura, Y., Simons, J. W., Dong, J.-T. Frequent somatic mutations of the transcription factor ATBF1 in human prostate cancer. Nature Genet. 37: 407-412, 2005. Note: Erratum: Nature Genet. 37: 652 only, 2005. [PubMed: 15750593] [Full Text: https://doi.org/10.1038/ng1528]
Wallenius, J., Kafantari, E., Jhaveri, E., Gorcenco, S., Ameur, A., Karremo, C., Dobloug, S., Karrman, K., de Koning, T., Ilinca, A., Landqvist Waldo, M., Arvidsson, A., Persson, S., Englund, E., Ehrencrona, H., Puschmann, A. Exonic trinucleotide repeat expansions in ZFHX3 cause spinocerebellar ataxia type 4: A poly-glycine disease. Am. J. Hum. Genet. 111: 1-14, 2024. [PubMed: 38035881] [Full Text: https://doi.org/10.1016/j.ajhg.2023.11.008]
Wictorin, K., Bradvik, B., Nilsson, K., Soller, M., van Westen, D., Bynke, G., Bauer, P., Schols, L., Puschmann, A. Autosomal dominant cerebellar ataxia with slow ocular saccades, neuropathy and orthostatism: a novel entity? Parkinsonism Relat. Disord. 20: 748-754, 2014. [PubMed: 24787759] [Full Text: https://doi.org/10.1016/j.parkreldis.2014.03.029]
Yamada, K., Ma, D., Miura, Y., Ido, A., Tamaoki, T., Yoshida, M. C. Assignment of the ATBF1 transcription factor gene (Atbf1) to mouse chromosome band 8E1 by in situ hybridization. Cytogenet. Cell Genet. 75: 30-31, 1996. [PubMed: 8995484] [Full Text: https://doi.org/10.1159/000134451]
Yamada, K., Miura, Y., Scheidl, T., Yoshida, M. C., Tamaoki, T. Assignment of the human ATBF1 transcription factor gene to chromosome 16q22.3-q23.1. Genomics 29: 552-553, 1995. [PubMed: 8666409] [Full Text: https://doi.org/10.1006/geno.1995.9967]