Alternative titles; symbols
HGNC Approved Gene Symbol: ATF6
Cytogenetic location: 1q23.3 Genomic coordinates (GRCh38): 1:161,766,320-161,964,070 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q23.3 | Achromatopsia 7 | 616517 | Autosomal recessive | 3 |
ATF6 is an endoplasmic reticulum (ER) stress-regulated transmembrane transcription factor that activates the transcription of ER molecules (summary by Shen et al., 2002).
An activating transcription factor (ATF)-binding site is a promoter element present in a wide range of viral and cellular genes. By screening a lambda-expression library with a DNA probe containing 3 tandem ATF-binding sites, Hai et al. (1989) obtained cDNAs encoding ATF1 through ATF8. Binding analysis showed that the incomplete ATF6 protein bound to a triplicated ATF site with low affinity but did not bind to a single ATF site.
Using a yeast interaction assay to screen a HeLa cell cDNA library for serum response factor (SRF; 600589)-interacting proteins, Zhu et al. (1997) cloned a sequence identical to a region of ATF6. The ATF6 sequence bound to the C terminus of SRF, outside the DNA-binding region. By 5-prime and 3-prime RACE, Zhu et al. (1997) obtained a full-length cDNA encoding ATF6. Sequence analysis predicted that the 670-amino acid protein contains an N-terminal serine-rich domain and a central DNA-binding domain followed by a leucine zipper sequence. Northern blot analysis revealed expression of a 2.5-kb transcript in HeLa cells and 4.5- and 8.0-kb transcripts in all mouse tissues tested, with the exception of spleen. Immunoblot analysis detected expression of a 90-kD protein in HeLa and COS cell lysates.
Ansar et al. (2015) identified 3 alternatively spliced isoforms of human ATF6: AK290498 and AF005887, both with 16 exons, and AB208929, with 14 exons. By RT-PCR, they demonstrated expression of all 3 isoforms in the human eye, particularly in retinal pigment epithelium (RPE) cells. The occurrence of multiple ATF6 isoforms was confirmed by Western blot analysis in adult C57BL/6J mouse retina. In CD1 mouse retina, ATF6 immunoreactivity was most prominent in the retinal ganglion cells, and staining was also observed in the RPE, outer and inner segments of photoreceptor cells, and inner and outer plexiform layers, as well as in the inner nuclear layer of neuronal retina.
The International Radiation Hybrid Mapping Consortium mapped the ATF6 gene to chromosome 1 (SHGC-32839). Meex et al. (2007) stated that the ATF6 gene maps to chromosome 1q23.3, the most replicated chromosomal locus for type 2 diabetes (125853).
Ansar et al. (2015) determined that the ATF6 gene comprises 16 exons.
When unfolded proteins accumulate in the endoplasmic reticulum, transcription of glucose-regulated proteins (GRPs) representing ER-resident molecular chaperones is markedly induced via the unfolded protein response (UPR) pathway. Yoshida et al. (1998) analyzed the promoter regions of the human GRP78 (HSPA5; 138120), GRP94 (191175), and calreticulin (CALR; 109091) genes and identified a novel element designated the 'ER stress response element,' or ERSE. ERSE, with a consensus of CCAATN9CCACG, was shown to be necessary and sufficient for induction of these GRPs. Using yeast 1-hybrid screening, Yoshida et al. (1998) isolated a human cDNA encoding a basic leucine zipper (bZIP) protein, ATF6, as a putative ERSE-binding protein. When overexpressed in HeLa cells, ATF6 enhanced transcription of GRP genes in an ERSE-dependent manner, whereas CREB-related protein (CREBRP; 600984), another bZIP protein closely related to ATF6, specifically inhibited GRP induction. Endogenous ATF6 constitutively expressed as a 90-kD protein was converted to a 50-kD protein in ER-stressed cells, which appeared to be important for the cellular response to ER stress.
Haze et al. (1999) found that in response to ER stress induced by thapsigargin, the 90-kD type II transmembrane glycoprotein form of ATF6 was converted to a 50-kD soluble nuclear form that retained only the N terminus, including the leucine zipper. Immunofluorescence analysis demonstrated that the subcellular localization altered from the ER to the nucleus for the form lacking the C terminus. Haze et al. (1999) determined that the transmembrane domain is located near the center of the protein, C terminal to the leucine zipper, at amino acids 378 to 398. Expression of the N-terminal 373 residues enhanced the levels of HSPA5 mRNA.
When unfolded proteins accumulate in the ER, ATF6 is cleaved to release its cytoplasmic domain, which enters the nucleus. Ye et al. (2000) showed that ATF6 is processed by site-1 protease (S1P; 603355) and site-2 protease (S2P; 300294), the enzymes that process sterol regulatory element-binding proteins (SREBPs; see 184756) in response to cholesterol deprivation. ATF6 processing was blocked completely in cells lacking S2P and partially in cells lacking S1P. ATF6 processing required RxxL and asparagine/proline motifs, known requirements for S1P and S2P processing, respectively. Cells lacking S2P failed to induce HSPA5, an ATF6 target, in response to ER stress. ATF6 processing did not require SREBP cleavage-activating protein (SCAP; 601510), which is essential for SREBP processing. Ye et al. (2000) concluded that S1P and S2P are required for the ER stress response as well as for lipid synthesis.
Li et al. (2000) found that in addition to its possible cleavage upon ER stress, optimal ATF6 stimulation requires at least 2 copies of the ERSEs and a functional NF-Y (see NFYA; 189903) complex with a high-affinity NF-Y-binding site that confers selectivity among different ERSEs. In thapsigargin-stressed cells, ATF6 interacted with YY1 (600013), which further enhanced and sustained the activity of ATF6.
Using immunoprecipitation, Shen et al. (2002) detected ATF6 binding to HSPA5, which dissociated in response to ER stress. Deletion of luminal HSPA5 binding sites or Golgi localization signals in ATF6 disrupted proper transport to the Golgi complex. The authors concluded that HSPA5 retains ATF6 in the ER by inhibiting its Golgi localization signals and that dissociation of HSPA5 during ER stress allows ATF6 to be transported to the Golgi. Sommer and Jarosch (2002) summarized the findings of Shen et al. (2002) and presented a discussion of the proteins involved in regulating levels of aberrant proteins within the ER.
The 3 UPR branches, governed by the ER stress sensors IRE1 (604033), PERK (604032), and ATF6, promote cell survival by reducing misfolded protein levels. UPR signaling also promotes apoptotic cell death if ER stress is not alleviated. Lin et al. (2007) found that IRE1 and ATF6 activities were attenuated by persistent ER stress in human cells. By contrast, PERK signaling, including translational inhibition and induction of the proapoptotic transcription regulator CHOP (126337), was maintained. When IRE1 activity was sustained artificially, cell survival was enhanced, suggesting a causal link between the duration of UPR branch signaling and life or death cell fate after ER stress. Key findings from their studies in cell culture were recapitulated in photoreceptors expressing mutant rhodopsin (180380) in animal models of retinitis pigmentosa.
Using HeLa cells, Higa et al. (2014) found that PDIA5 (616942) played a crucial role in disulfide bond rearrangement and activation of ATF6 upon imatinib-induced ER stress. In leukemia cell lines, knockdown of ATF6 or PDIA5 via small interfering RNA, or pharmacologic inhibition of PDI, blocked ATF6 activation and release from the ER and restored cell sensitivity to imatinib. Silencing of PDIA5 did not significantly affect activation of other arms of the unfolded protein response.
Achromatopsia 7
In affected individuals from a consanguineous Pakistani family with achromatopsia (ACHM7; 616517), Ansar et al. (2015) identified homozygosity for a 1-bp duplication in the ATF6 gene (605537.0001). The mutation, which segregated with disease in the family, was not found in ethnically matched controls or public databases. Functional studies showed mislocalization of the mutant protein compared to wildtype.
From a cohort of 304 patients with achromatopsia, Kohl et al. (2015) identified 18 patients from 10 independent families who were homozygous or compound heterozygous for mutations in the ATF6 gene (see, e.g., 605537.0002-605537.0006). Functional analysis demonstrated that the mutations attenuate ATF6 transcriptional activity in response to ER stress. Kohl et al. (2015) concluded that mutations in ATF6 are a rare cause of achromatopsia and, noting that all 18 mutation-positive patients exhibited marked foveal hypoplasia, suggested that severe foveal hypoplasia with a poorly formed or absent foveal pit could be a hallmark of ATF6-related disease.
Type 2 Diabetes
Thameem et al. (2006) reported a nominal association between variants of the ATF6 gene and type 2 diabetes (125853) in Pima Indians (p less than 0.05).
Meex et al. (2007) investigated 16 ATF6 polymorphisms for their contribution to disturbed glucose homeostasis and type 2 diabetes in Dutch Caucasians. They found that common ATF variants were associated with elevated glucose levels in the general population (p = 0.005-0.5), and that the majority of these variants, and haplotypes thereof, were significantly associated with impaired fasting glucose, impaired glucose tolerance, and type 2 diabetes (p = 0.006-0.05). They noted that the associated variants differed from those identified by Thameem et al. (2006) in Pima Indians and that the variants identified by Thameem et al. (2006) were not significantly associated with fasting glucose levels, disturbed glucose homeostasis, or type 2 diabetes in their Dutch Caucasian cohorts.
Kohl et al. (2015) observed no significant differences in retinal morphology and function in young Atf6-null mice compared to heterozygous or wildtype littermates. However, at 18 months of age, both rod and cone single-flash electroretinography (ERG) responses were markedly reduced in the Atf6-null mice compared to wildtype mice; fundi of the mutant mice also showed retinal degeneration in areas that correlated with hyperfluorescent spots on confocal scanning-laser ophthalmoscopy. Retinal vasculature appeared unaffected in the mouse model, as observed in human patients. Spectral-domain optical coherence tomography (SD-OCT) imaging showed disruption of the layers corresponding to the inner and outer segments; however, in contrast to human patients, the RPE was also affected in mice. Noting that mice do not develop foveas, Kohl et al. (2015) suggested that there are profound differences in the function and impact of ATF6 in mouse and human retinal development and maintenance.
In 4 affected individuals from a consanguineous Pakistani family with achromatopsia (ACHM7; 616517), Ansar et al. (2015) identified homozygosity for a 1-bp duplication (c.355_356dupG, NM_007348.3) in exon 5 of the ATF6 gene, causing a frameshift predicted to result in a premature termination codon (Glu119GlyfsTer8) prior to the basic region leucine zipper (BRLZ) and transmembrane domains, affecting all 3 ATF6 isoforms. The mutation, which segregated with disease in the family, was not found in 470 ethnically matched control chromosomes, in exome sequence data from 130 unrelated Pakistani individuals without eye disease, or in the dbSNP or ExAC databases. Functional analysis in transfected COS-7 cells demonstrated expression of wildtype ATF6 throughout the cytoplasm with localization to the ER, whereas the Glu119GlyfsTer8 mutant had significantly reduced localization in the cytoplasm and was mainly confined to the nucleus. Western blot analysis confirmed that mutant ATF6 had a reduced protein size.
In 3 sibs from a nonconsanguineous Irish family and 3 sibs from a nonconsanguineous United Kingdom family, all exhibiting achromatopsia (ACHM7; 616517), Kohl et al. (2015) identified homozygosity for a c.970C-T transition in the ATF6 gene (c.970C-T, NM_007348.3), resulting in an arg324-to-cys (R324C) substitution at a highly conserved residue in the basic region of the bZIP domain, necessary for dimerization. The mutation, which segregated with disease in both families, was not found in an in-house database or the dbSNP or Exome Variant Server databases. However, the c.970C-T allele was observed in heterozygosity in 3 of 120,904 genotypes found in the ExAC browser. Haplotype reconstruction of SNP chip data from the 2 families indicated that all carriers of the R324C mutation shared a 0.7-Mb common homozygous haplotype flanked by rs4072409 and rs16840028, suggestive of either a founder mutation in the Irish and UK population or identity by descent. Functional analysis in patient fibroblasts and in transfected HEK293 cells showed significantly reduced or absent mRNA induction of downstream transcriptional targets with the R324C mutant compared to wildtype ATF6.
In affected individuals from 3 French Canadian families with achromatopsia (AHM7; 616517), Kohl et al. (2015) identified homozygosity for a splice site mutation (c.1533+1G-C, NM_007348.3) in intron 12 of the ATF6 gene, resulting in 2 aberrantly spliced proteins. Sequencing revealed that the larger mutant protein was due to retention of 83 bp of intron 12, causing a premature termination codon (Gly512LeufsTer39), whereas the smaller mutation was due to skipping of exon 12, which also resulted in premature termination (Leu479ValfsTer11). The mutation, which segregated with disease in the families, was not found in an in-house database or the dbSNP, Exome Variant Server, or ExAC databases. All patients carrying the splice site mutation had the same homozygous SNP genotype based on 2 rare SNPs, rs371893818 and rs374093774, suggestive of a founder mutation in the French Canadian population. One of the French Canadian patients, a 17-year-old boy, exhibited incomplete achromatopsia.
In a German brother and sister with achromatopsia (ACHM7; 616517), Kohl et al. (2015) identified compound heterozygosity for 2 different 1-bp duplications in the ATF6 gene: c.797dupC (c.797dupC, NM_007348.3), resulting in an asn267-to-ter (N267X) substitution, and c.1110dupA (605537.0005), causing a frameshift resulting in a premature termination codon (Val371SerfsTer3). The mutations, which segregated with disease in the family, were not found in an in-house database or the dbSNP, Exome Variant Server, or ExAC databases.
For discussion of the c.1110dupA mutation in the ATF6 gene (c.1110dupA, NM_007348.3) that was found in compound heterozygous state in 2 German sibs with achromatopsia (ACHM7; 616517) by Kohl et al. (2015), see 605537.0004.
In a 26-year-old Iranian woman with incomplete achromatopsia (ACHM7; 616517), Kohl et al. (2015) identified homozygosity for a c.1699T-A transversion in the ATF6 gene (c.1699T-A, NM_007348.3), resulting in a tyr567-to-asn (Y567N) substitution at a highly conserved residue within an 18-residue C-terminal sequence motif that is present in both ATF6A and ATF6B (600984). The mutation, which segregated with disease in the family, was not found in an in-house database or the dbSNP, Exome Variant Server, or ExAC databases.
Ansar, M., Santos-Cortez, R. L. P., Saqib, M. A. N., Zulfiqar, F., Lee, K., Ashraf, N. M., Ullah, E., Wang, X., Sajid, S., Khan, F. S., Amin-ud-Din, M., University of Washington Center for Mendelian Genomics, and 9 others. Mutation of ATF6 causes autosomal recessive achromatopsia. Hum. Genet. 134: 941-950, 2015. [PubMed: 26063662] [Full Text: https://doi.org/10.1007/s00439-015-1571-4]
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Haze, K., Yoshida, H., Yanagi, H., Yura, T., Mori, K. Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. Molec. Biol. Cell 10: 3787-3799, 1999. [PubMed: 10564271] [Full Text: https://doi.org/10.1091/mbc.10.11.3787]
Higa, A., Taouji, S., Lhomond, S., Jensen, D., Fernandez-Zapico, M. E., Simpson, J. C., Pasquet, J.-M., Schekman, R., Chevet, E. Endoplasmic reticulum stress-activated transcription factor ATF6-alpha requires the disulfide isomerase PDIA5 to modulate chemoresistance. Molec. Cell. Biol. 34: 1839-1849, 2014. [PubMed: 24636989] [Full Text: https://doi.org/10.1128/MCB.01484-13]
Kohl, S., Zobor, D., Chiang, W.-C., Weisschuh, N., Staller, J., Gonzalez Menendez, I., Chang, S., Beck, S. C., Garcia Garrido, M., Sothilingam, V., Seeliger, M. W., Stanzial, F., and 21 others. Mutations in the unfolded protein response regulator ATF6 cause the cone dysfunction disorder achromatopsia. Nature Genet. 47: 757-765, 2015. [PubMed: 26029869] [Full Text: https://doi.org/10.1038/ng.3319]
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Meex, S. J. R., van Greevenbroek, M. M. J., Ayoubi, T. A., Vlietinck, R., van Vliet-Ostaptchouk, J. V., Hofker, M. H., Vermeulen, V. M. M.-J., Schalkwijk, C. G., Feskens, E. J. M., Boer, J. M. A., Stehouwer, C. D. A., van der Kallen, C. J. H., de Bruin, T. W. A. Activating transcription factor 6 polymorphisms and haplotypes are associated with impaired glucose homeostasis and type 2 diabetes in Dutch Caucasians. J. Clin. Endocr. Metab. 92: 2720-2725, 2007. [PubMed: 17440018] [Full Text: https://doi.org/10.1210/jc.2006-2280]
Shen, J., Chen, X., Hendershot, L., Prywes, R. ER stress regulation of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking of Golgi localization signals. Dev. Cell 3: 99-111, 2002. [PubMed: 12110171] [Full Text: https://doi.org/10.1016/s1534-5807(02)00203-4]
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Thameem, F., Farook, V. S., Bogardus, C., Prochazka, M. Association of amino acid variants in the activating transcription factor 6 gene (ATF6) on 1q21-q23 with type 2 diabetes in Pima Indians. Diabetes 55: 839-842, 2006. [PubMed: 16505252] [Full Text: https://doi.org/10.2337/diabetes.55.03.06.db05-1002]
Ye, J., Rawson, R. B., Komuro, R., Chen, X., Dave, U. P., Prywes, R., Brown, M. S., Goldstein, J. L. ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs. Molec. Cell 6: 1355-1364, 2000. [PubMed: 11163209] [Full Text: https://doi.org/10.1016/s1097-2765(00)00133-7]
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Zhu, C., Johansen, F.-E., Prywes, R. Interaction of ATF6 and serum response factor. Molec. Cell. Biol. 17: 4957-4966, 1997. [PubMed: 9271374] [Full Text: https://doi.org/10.1128/MCB.17.9.4957]