Alternative titles; symbols
HGNC Approved Gene Symbol: SET
Cytogenetic location: 9q34.11 Genomic coordinates (GRCh38) : 9:128,683,424-128,696,396 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q34.11 | Intellectual developmental disorder, autosomal dominant 58 | 618106 | Autosomal dominant | 3 |
The SET gene encodes a widely expressed multifunctional nuclear protein that is involved in chromatin remodeling and gene transcription (summary by Hamdan et al., 2014) and is thought to play a role in neurogenesis and neuronal differentiation (summary by Stevens et al., 2018).
SET belongs to a family of acidic domain-containing proteins that interact with the lysine-rich domains of transcriptional regulators in an acetylation-dependent manner and inhibit their function (Wang et al., 2016).
The translocation (6;9)(p23q34) is the hallmark of a specific subtype of acute myeloid leukemia (AML) characterized by a poor prognosis and a young age of onset. It is classified in the French-American-British (FAB) system mostly as M2/M4 and rarely as M1 or refractive anemia with excess of blast cells (RAEB). On chromosome 9, breakpoints take place in a specific intron, denoted icb-9, of a large gene named Cain (CAN; 114350). On chromosome 6, breakpoints occur in a single intron, icb-6, of a gene named DEK (125264). In a patient with acute undifferentiated leukemia and an apparently normal karyotype, von Lindern et al. (1992) found a breakpoint in icb-9 of the CAN gene in a bone marrow sample but detected no breakpoint in DEK. They isolated and characterized a novel gene, named SET (suppressor of variegation, enhancer of zeste, and Trithorax), that was fused to CAN in the leukemic cells of this patient. A chimeric SET-CAN transcript whose sequence predicted a fusion protein of 155 kD was detected. The SET gene encodes transcripts of 2.0 and 2.7 kb that result from the use of alternative polyadenylation sites. Both transcripts contained the open reading frame for a putative protein with a predicted molecular mass of 32 kD. The SET sequence showed homology with the yeast nucleosome assembly protein NAP-I. The only common sequence motif of SET and DEK proteins is an acidic region. SET has a long acidic tail, of which a large part is present in the predicted SET-CAN fusion protein.
Carlson et al. (1998) studied the role of SET in the regulation of renal cell proliferation and tumorigenesis. The mRNA encoding SET was expressed at much higher levels in transformed human and rodent cell lines than in cultured renal epithelial and primary endothelial cells. Consistent with a role for SET in cell proliferation, SET mRNA expression was markedly reduced in cells rendered quiescent by serum starvation, contact inhibition, or differentiation. Previous findings during renal development were extended by demonstrating that SET protein expression is also much greater in developing rat and human kidney than in fully differentiated, mature kidney. Finally, high levels of SET mRNA and SET protein expression were found in Wilms tumor but not in renal cell carcinoma, adult polycystic kidney disease, or in transitional cell carcinoma. The SET domain (Tschiersch et al., 1994) is found in proteins that are involved in embryonic development (Tripoulas et al., 1996).
Granzyme A (GZMA; 140050) induces a caspase-independent cell death pathway characterized by single-stranded DNA nicks and other features of apoptosis. A GZMA-activated DNase (GAAD) is in an endoplasmic reticulum-associated complex containing pp32 (600832) and the GZMA substrates SET, HMG2 (163906), and APE1 (107748). Fan et al. (2003) showed that GAAD is NM23H1 (156490), a nucleoside diphosphate kinase implicated in suppression of tumor metastasis, and its specific inhibitor (IGAAD) is SET. NM23H1 bound SET and was released from inhibition by GZMA cleavage of SET. After GZMA loading or cytotoxic T lymphocyte attack, SET and NM23H1 translocated to the nucleus and SET was degraded, allowing NM23H1 to nick chromosomal DNA. GZMA-treated cells with silenced NM23H1 expression were resistant to GZMA-mediated DNA damage and cytolysis, while cells overexpressing NM23H1 were more sensitive.
By yeast 2-hybrid analysis using the N-terminal 277 amino acids of SET as bait, Minakuchi et al. (2001) identified SET-binding protein-1 (SETBP1; 611060). Deletion and mutagenesis analysis revealed that amino acids 182 to 223 of SET interacted with amino acids 1238 to 1434 of SETBP1. Immunoprecipitation analysis verified that SETBP1 interacted with endogenous SET in a human osteosarcoma cell line.
Ischemia and seizure cause excessive neuronal excitation that is associated with brain acidosis and neuronal cell death. Liu et al. (2008) found that the neurotoxin kainic acid activated lysosomal asparagine endopeptidase (AEP, or LGMN; 602620) in mouse brain and triggered degradation of Set, followed by DNA nicking and neuronal cell death. Pike-L (CENTG1; 605476) strongly bound Set in the nucleus and protected Set from proteolytic cleavage by Aep in vitro and in vivo, thereby diminishing DNA damage and neuronal cell death. Kainic acid or stroke failed to provoke DNA nicking and neuronal cell death in Aep-deficient mice.
DNA damage results in acetylation of lysines in the C-terminal domain of the proapoptotic transcriptional activator p53 (TP53; 191170). Wang et al. (2016) found that acidic domain-containing proteins, including SET, DAXX (603186), PELP1 (609455), and VPRBP (DCAF1; 617259), bound the deacetylated C-terminal domain of p53 in human cell lines and repressed p53 function. Acetylation of p53 upon DNA damage disrupted the p53-SET interaction and activated p53. The acidic domain of SET also interacted with the deacetylated, but not acetylated, lysine-rich domains of H3 (see 602810), Ku70 (XRCC6; 152690), and FOXO1 (FOXO1A; 136533).
By fluorescence in situ hybridization, von Lindern et al. (1992) assigned the SET gene to 9q34, centromeric of ABL (189980).
In 6 patients, including a mother and son, with autosomal dominant intellectual developmental disorder-58 (MRD58; 618106), Stevens et al. (2018) identified heterozygous mutations in the SET gene (see, e.g., 600960.0001-600960.0004). The mutations were found by exome sequencing and the patients were ascertained through collaborative efforts of clinical genetics laboratories. All of the mutations occurred de novo, except in 1 family (the mother and son), and all were predicted to affect the 4 SET transcript isoforms. Stevens et al. (2018) noted that de novo heterozygous loss-of-function SET mutations had previously been found in 3 unrelated patients with intellectual disability in the Deciphering Developmental Disorders Study (2017) and in 1 patient with intellectual disability in a large study by Hamdan et al. (2014) (see 600960.0005). Functional studies of the variants and studies of patient cells were not performed, but all mutations were predicted to result in a loss of function and haploinsufficiency. Stevens et al. (2018) stated that SET plays a role in neurogenesis and neuronal differentiation. The findings suggested that disruption of epigenetic regulatory modules can lead to intellectual disability.
In a 16-year-old boy and his 49-year-old mother (patients 1a and 1b) with autosomal dominant intellectual developmental disorder-58 (MRD58; 618106), Stevens et al. (2018) identified a heterozygous 4-bp deletion (c.167_170del, NM_001122821.1) in exon 2 of the SET gene, predicted to result in a frameshift and premature termination (Arg57LeufsTer10). The mutation, which was found by whole-exome sequencing, occurred de novo in the mother. Stevens et al. (2018) noted that the same de novo heterozygous 4-bp deletion in the SET gene had previously been found in 2 unrelated patients with intellectual disability in the Deciphering Developmental Disorders Study (2017). Functional studies of the variant and studies of patient cells were not performed; however, the variant was predicted to result in a loss of function and haploinsufficiency.
In 5.5-year-old boy (patient 2) with autosomal dominant intellectual developmental disorder-58 (MRD58; 618106), Stevens et al. (2018) identified a de novo heterozygous c.283T-G transversion (c.283T-G, NM_001122821.1) in exon 3 of the SET gene, resulting in a trp95-to-gly (W95G) substitution at a highly conserved residue in the NAP domain, which is responsible for core histone and dsDNA binding. The mutation was found by exome sequencing. Functional studies of the variant and studies of patient cells were not performed.
In a 4-year-old boy (patient 3) with autosomal dominant intellectual developmental disorder-58 (MRD58; 618106), Stevens et al. (2018) identified a de novo heterozygous c.352C-T transition (c.352C-T, NM_001122321.1) in exon 4 of the SET gene, resulting in a his118-to-tyr (H118Y) substitution at a highly conserved residue in the NAP domain, which is responsible for core histone and dsDNA binding. The mutation was found by exome sequencing. Functional studies of the variant and studies of patient cells were not performed.
In a 5-year-old boy (patient 5) with autosomal dominant intellectual developmental disorder-58 (MRD58; 618106), Stevens et al. (2018) identified a de novo heterozygous 2-bp duplication (c.689_690dup, NM_001122821.1) in exon 6 of the SET gene, resulting in a frameshift and premature termination (Gln231TyrfsTer29). The mutation was found by exome sequencing. Functional studies of the variant and studies of patient cells were not performed.
In a 12-year-old boy (patient 115.81) with autosomal dominant intellectual developmental disorder-58 (MRD58; 618106), Hamdan et al. (2014) identified a de novo heterozygous 3-bp deletion (c.699_701delCTT, NM_001122821.1) in the SET gene, predicted to result in a frameshift and premature termination (Tyr233Ter). The mutation was not found in the Exome Variant Server database; functional studies of the variant and studies of patient cells were not performed. The patient was part of a cohort of 41 child-parent trios, in which the child had intellectual disability, who underwent exome sequencing.
Carlson, S. G., Eng, E., Kim, E.-G., Perlman, E. J., Copeland, T. D., Ballermann, B. J. Expression of SET, an inhibitor of protein phosphatase 2A, in renal development and Wilms' tumor. J. Am. Soc. Nephrol. 9: 1873-1880, 1998. [PubMed: 9773788] [Full Text: https://doi.org/10.1681/ASN.V9101873]
Deciphering Developmental Disorders Study. Prevalence and architecture of de novo mutations in developmental disorders. Nature 542: 433-438, 2017. [PubMed: 28135719] [Full Text: https://doi.org/10.1038/nature21062]
Fan, Z., Beresford, P. J., Oh, D. Y., Zhang, D., Lieberman, J. Tumor suppressor NM23-H1 is a granzyme A-activated DNase during CTL-mediated apoptosis, and the nucleosome assembly protein SET is its inhibitor. Cell 112: 659-672, 2003. Note: Erratum: Cell 115: 241 only, 2003. [PubMed: 12628186] [Full Text: https://doi.org/10.1016/s0092-8674(03)00150-8]
Hamdan, F. F., Srour, M., Capo-Chichi, J.-M., Daoud, H., Nassif, C., Patry, L., Massicotte, C., Ambalavanan, A., Spiegelman, D., Diallo, O., Henrion, E., Dionne-Laporte, A., Fougerat, A., Pshezhetsky, A. V., Venkateswaran, S., Rouleau, G. A., Michaud, J. L. De novo mutations in moderate or severe intellectual disability. PLoS Genet. 10: e1004772, 2014. Note: Electronic Article. [PubMed: 25356899] [Full Text: https://doi.org/10.1371/journal.pgen.1004772]
Liu, Z., Jang, S.-W., Liu, X., Cheng, D., Peng, J., Yepes, M., Li, X., Matthews, S., Watts, C., Asano, M., Hara-Nishimura, I., Luo, H. R., Ye, K. Neuroprotective actions of PIKE-L by inhibition of SET proteolytic degradation by asparagine endopeptidase. Molec. Cell 29: 665-678, 2008. [PubMed: 18374643] [Full Text: https://doi.org/10.1016/j.molcel.2008.02.017]
Minakuchi, M., Kakazu, N., Gorrin-Rivas, M. J., Abe, T., Copeland, T. D., Ueda, K., Adachi, Y. Identification and characterization of SEB, a novel protein that binds to the acute undifferentiated leukemia-associated protein SET. Europ. J. Biochem. 268: 1340-1351, 2001. [PubMed: 11231286] [Full Text: https://doi.org/10.1046/j.1432-1327.2001.02000.x]
Stevens, S. J. C., van der Schoot, V., Leduc, M. S., Rinne T., Lalani, S. R., Weiss, M. M., van Hagen, J. M., Lachmeijer, A. M. A., CAUSES Study, Stockler-Ipsiroglu, S. G., Lehman, A., Brunner, H. G. De novo mutations in the SET nuclear proto-oncogene, encoding a component of the inhibitor of histone acetyltransferases (INHAT) complex in patients with nonsyndromic intellectual disability. Hum. Mutat. 39: 1014-1023, 2018. [PubMed: 29688601] [Full Text: https://doi.org/10.1002/humu.23541]
Tripoulas, N., LaJeunesse, D., Gildea, J., Shearn, A. The Drosophila ash1 gene product, which is localized at specific sites on polytene chromosomes, contains a SET domain and a PHD finger. Genetics 143: 913-928, 1996. [PubMed: 8725238] [Full Text: https://doi.org/10.1093/genetics/143.2.913]
Tschiersch, B., Hofmann, A., Krauss, V., Dorn, R., Korge, G., Reuter, G. The protein encoded by the Drosophila position-effect variegation suppressor gene Su(var)3-9 combines domains of antagonistic regulators of homeotic gene complexes. EMBO J. 13: 3822-3831, 1994. [PubMed: 7915232] [Full Text: https://doi.org/10.1002/j.1460-2075.1994.tb06693.x]
von Lindern, M., van Baal, S., Wiegant, J., Raap, A., Hagemeijer, A., Grosveld, G. 'Can,' a putative oncogene associated with myeloid leukemogenesis, may be activated by fusion of its 3-prime half to different genes: characterization of the 'set' gene. Molec. Cell. Biol. 12: 3346-3355, 1992. [PubMed: 1630450] [Full Text: https://doi.org/10.1128/mcb.12.8.3346-3355.1992]
Wang, D., Kon, N., Lasso, G., Leng, W., Zhu, W.-G., Qin, J., Honig, B., Gu, W. Acetylation-regulated interaction between p53 and SET reveals a widespread regulatory mode. Nature 538: 118-122, 2016. [PubMed: 27626385] [Full Text: https://doi.org/10.1038/nature19759]