Alternative titles; symbols
HGNC Approved Gene Symbol: SETD1B
Cytogenetic location: 12q24.31 Genomic coordinates (GRCh38) : 12:121,790,155-121,832,656 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q24.31 | Intellectual developmental disorder with seizures and language delay | 619000 | Autosomal dominant | 3 |
The SETD1B gene encodes a catalytic SET domain protein of the histone methyltransferase complex, which mediates methylation of H3K4 sites to play a role in the epigenetic regulation of gene transcription (summary by Lee et al., 2007; Hiraide et al., 2018).
By sequencing clones obtained from a size-fractionated adult brain cDNA library, Kikuno et al. (1999) cloned SETD1B, which they designated KIAA1076. RT-PCR ELISA detected wide expression of SETD1B, with highest expression in ovary and testis.
By database analysis, Lee et al. (2007) found that the 1,923-amino acid SET1B protein shares 39% and 37% sequence identity with human SET1A (SETD1A; 611052) and S. cerevisiae Set1, respectively. Like SET1A, SET1B contains conserved SET and post-SET domains in the C terminus and an RNA recognition domain in the N terminus, but it lacks the HCF1-binding motif of SETD1A.
By radiation hybrid analysis, Kikuno et al. (1999) mapped the SETD1B gene to chromosome 12. Scott (2007) mapped the gene to 12q24.31 based on an alignment of the SETD1B sequence (GenBank AB028999) with the genomic sequence (build 36.2).
By immunoprecipitation and mass spectrometry, Lee et al. (2007) showed that SET1B associates with an approximately 450-kD complex that contains all 5 noncatalytic components of the SET1A complex, including CXXC1 (609150), RBBP5 (600697), ASH2 (604782), WDR5 (609012), and WDR82 (611059). In vitro assays demonstrated that the SET1B complex is a histone methyltransferase that produces trimethylated histone H3 at Lys4. Inducible expression of the C terminus of either SET1A or SET1B decreased steady state levels of both endogenous SET1A and SET1B protein, but did not alter the expression of the noncatalytic components of the SET1 complexes. Confocal microscopy revealed that the SET1A and SET1B proteins localize to a largely nonoverlapping set of euchromatic nuclear speckles. Lee et al. (2007) suggested that each protein binds to a unique set of target genes and that the proteins make nonredundant contributions to the epigenetic control of chromatin structure and gene expression.
Li et al. (2016) demonstrated that a minimized human RBBP5-ASH2L heterodimer is the structural unit that interacts with and activates all MLL family histone methyltransferases (MLL1, 159555; MLL2, 602113; MLL3, 606833; MLL4, 606834; SET1A, 611052; SET1B). Their structural, biochemical, and computational analyses revealed a 2-step activation mechanism of MLL family proteins. Li et al. (2016) concluded that their findings provided unprecedented insights into the common theme and functional plasticity in complex assembly and activity regulation of MLL family methyltransferases, and also suggested a universal regulation mechanism for most histone methyltransferases.
Using a CRISPR screen, Ortmann et al. (2021) identified human SET1B as a gene required to activate hypoxia-inducible transcription factors (HIFs; see 603348). RNA-sequencing analysis showed that SET1B selectively drove mRNA expression of HIF target genes in hypoxia. However, SET1B was involved in a more global transcriptional regulation, as SET1B loss led to decreased mRNA expression of both HIF target and control genes, resulting in impaired cell growth, angiogenesis of hypoxia-exposed HeLa or A549 cells, and tumor establishment in xenograft mouse models in hypoxia. SET1B interacted with the HIF heterodimer, and the interaction required both PAS domains of HIF1-alpha (HIF1A; 603348). Under hypoxia conditions, SET1B accumulated in nucleus and was recruited to chromatin through interaction with the HIF heterodimer for activation of select HIF target genes. On chromatin, SET1B was involved in histone methylation of a subset of HIF target loci by selectively inducing H3K4 trimethylation.
In 2 unrelated Japanese patients with intellectual developmental disorder with seizures and language delay (IDDSELD; 619000), Hiraide et al. (2018) identified de novo heterozygous missense mutations in the SETD1B gene (R1842W, 611055.0001; R1859C, 611055.0002). The mutations, which were found by trio-based whole-exome sequencing and confirmed by Sanger sequencing, were not present in several public databases, including dbSNP (build 137), 1000 Genomes Project, and ExAC. Functional studies of the variants and studies of patient cells were not performed. The patients were part of a cohort of 337 individuals with childhood-onset epilepsy who underwent trio-based whole-exome sequencing. In addition to the mutation in the SETD1B gene, patient 2, who had a more severe phenotype, carried additional variants in 4 other genes that may have contributed to the disorder.
In a Japanese girl with IDDSELD, Den et al. (2019) identified a de novo heterozygous frameshift mutation in the last exon of the SETD1B gene (611055.0003) that was demonstrated to escape nonsense-mediated mRNA decay and predicted to produce a truncated protein. Additional functional studies were not performed, but the findings suggested a possible gain-of-function effect. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in multiple public databases, including gnomAD.
In 3 unrelated patients with IDDSELD, Krzyzewska et al. (2019) identified heterozygous mutations in the SETD1B gene (611055.0001-611055.0002; R1301X, 611055.0004). Two of the mutations occurred de novo; the inheritance pattern in the third patient was unknown. The mutations were detected by whole-exome sequencing, and some of the patients were found through the GeneMatcher program. Using differential analysis to study patient DNA, Krzyzewska et al. (2019) found a shift of the genomewide methylation status toward hypermethylation compared to controls. This 'episignature' was unique to patients with SETD1B mutations when compared to patients with other neurodevelopmental disorders associated with methylation changes. The authors postulated a loss-of-function effect of the mutations.
In 4 unrelated patients with IDDSELD, Roston et al. (2021) identified 4 different de novo heterozygous mutations in the SETD1B gene (see, e.g., 611055.0005-611055.0007). The mutations were found by exome or genome sequencing. The variants included 2 nonsense, 1 splice site, and 1 missense. Functional studies of the variants and studies of patient cells were not performed.
Weerts et al. (2021) identified mutations in the SETD1B gene in 36 patients with neurodevelopmental disorders. Thirty-two patients had heterozygous mutations, of which 28 occurred de novo, 1 was inherited from an affected parent, and 1 was inherited from an unaffected parent; the inheritance pattern of 2 was unknown. Of the heterozygous mutations, 14 were considered to be pathogenic (see, e.g., 611055.0008-611055.0012) and 10 were considered to be likely pathogenic. Four patients (patients 3, 4, 11, and 12) from 3 families had biallelic variants of unknown significance in the SETD1B gene, which were inherited from unaffected carrier parents. Weerts et al. (2021) hypothesized that the biallelic variants, in combination, could reduce SETD1B function below a required threshold, leading to a phenotype.
In a 12-year-old Japanese girl (patient 1) with intellectual developmental disorder with seizures and language delay (IDDSELD; 619000), Hiraide et al. (2018) identified a de novo heterozygous c.5524C-T transition (c.5524C-T, NM_015048.1) in the SETD1B gene, resulting in an arg1842-to-trp (R1842W) substitution at a conserved residue in the C-terminal SET domain. The mutation, which was found by trio-based whole-exome sequencing and confirmed by Sanger sequencing, was not present in several public databases, including dbSNP (build 137), 1000 Genomes Project, and ExAC. Functional studies of the variant and studies of patient cells were not performed.
In a 7-year-old boy (patient 5) with IDDSELD, Krzyzewska et al. (2019) identified a heterozygous arg188-to-trp (R1885W) mutation in the SETD1B gene, which was the same mutation as that reported by Hiraide et al. (2018).
In a 34-year-old Japanese man (patient 2) with intellectual developmental disorder with seizures and language delay (IDDSELD; 619000), Hiraide et al. (2018) identified a de novo heterozygous c.5575C-T transition (c.5575C-T, NM_015048.1) in the SETD1B gene, resulting in an arg1859-to-cys (R1859C) substitution at a conserved residue in the C-terminal SET domain. The mutation, which was found by trio-based whole-exome sequencing and confirmed by Sanger sequencing, was not present in several public databases, including dbSNP (build 137), 1000 Genomes Project, and ExAC. Functional studies of the variant and studies of patient cells were not performed. This patient also carried additional variants in 4 other genes that may have contributed to the disorder.
In a 16-year-old boy (patient 2) with IDDSELD, Krzyzewska et al. (2019) identified a de novo heterozygous arg1902-to-cys (R1902C) mutation in the SETD1B gene, which was the same mutation as that reported by Hiraide et al. (2018).
In a Japanese girl with intellectual developmental disorder with seizures and language delay (IDDSELD; 619000), Den et al. (2019) identified a de novo heterozygous 4-bp deletion (c.5644_5647delATAG, NM_015048.1) in exon 17 of the SETD1B gene, resulting in a frameshift and premature termination (Ile1882SerfsTer118). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in multiple public databases, including gnomAD. The mutation, which occurred in the last exon, was demonstrated to escape nonsense-mediated mRNA decay and predicted to produce a truncated protein. Additional functional studies were not performed, but the findings suggested a possible gain-of-function effect.
In a 13-year-old boy (patient 1) with intellectual developmental disorder with seizures and language delay (IDDSELD; 619000), Krzyzewska et al. (2019) identified a de novo heterozygous mutation in the SETD1B gene, resulting in an arg1301-to-ter (R1301X) substitution. The authors predicted a loss-of-function effect.
In a 12-year-old boy (patient 4) with intellectual developmental disorder with seizures and language delay (IDDSELD; 619000), Roston et al. (2021) identified a de novo heterozygous c.2932C-T transition (c.2932C-T, NM_015048.1) in the SETD1B gene, resulting in a gln978-to-ter (Q978X) substitution. The mutation was found by exome sequencing. Functional studies of the variant and studies of patient cells were not performed.
In a 19-year-old woman (patient 2) with intellectual developmental disorder with seizures and language delay (IDDSELD; 619000), Roston et al. (2021) identified a de novo heterozygous c.3964C-T transition (c.3964C-T, NM_015048.1) in the SETD1B gene, resulting in a gln1322-to-ter (Q1322X) substitution. The mutation was found by exome sequencing. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in nonsense-mediated mRNA decay and a loss of function.
In a 3.5-year-old boy (patient 3) with intellectual developmental disorder with seizures and language delay (IDDSELD; 619000), Roston et al. (2021) identified a de novo heterozygous c.5833T-C transition (c.5833T-C, NM_001353345.1) in the SETD1B gene, resulting in a phe1945-to-leu (F1945L) substitution. The mutation was found by exome sequencing. Functional studies of the variant and studies of patient cells were not performed.
In a 44-year-old man (patient 33) with intellectual developmental disorder with seizures and language delay (IDDSELD; 619000), Weerts et al. (2021) identified a de novo heterozygous c.5842G-A transition (c.5842G-A, NM_001353345) in the SETD1B gene, resulting in a glu1948-to-lys (E1948K) substitution. The mutation was identified by whole-exome sequencing. SETD1B with the E1948K mutation was expressed in HEK293 cells and had lower colocalization with the COMPASS subunit ASH2 compared to wildtype. The DNA methylation pattern identified in the patient was consistent with the episignature reported in other patients with pathogenic SETD1B mutations.
In a 22-year-old man (patient 31) with intellectual developmental disorder with seizures and language delay (IDDSELD; 619000), Weerts et al. (2021) identified a de novo heterozygous c.5702C-A transversion (c.5702C-A, NM_01353345) in the SETD1B gene, resulting in an ala1902-to-glu (A1901E) substitution. The mutation was identified by whole-exome sequencing. SETD1B protein with the A1901E mutation had abnormal thermal stability. The DNA methylation pattern identified in the patient was consistent with the episignature reported in other patients with pathogenic SETD1B mutations.
In a 7-year-old girl (patient 5) with intellectual developmental disorder with seizures and language delay (IDDSELD; 619000), Weerts et al. (2021) identified a de novo heterozygous c.284_286delinsA mutation (c.284_286delinsA, NM_001353345) in the SETD1B gene, resulting in a phe95-to-ter (F95X) substitution. The mutation was identified by whole-exome sequencing. The DNA methylation pattern identified in the patient was consistent with the episignature reported in other patients with pathogenic SETD1B mutations.
In a 30-year-old man (patient 7) with intellectual developmental disorder with seizures and language delay (IDDSELD; 619000), Weerts et al. (2021) identified a de novo heterozygous 27-bp inversion (c.337_363inv, NM_001353345) in the SETD1B gene, resulting in an asn113_asp121delins9 deletion/insertion. The mutation was identified by whole-exome sequencing. Expression of SETD1B with the c.337_363inv in HEK293 cells showed that the mutant protein failed to properly localize to the nucleus. The DNA methylation pattern identified in the patient was consistent with the episignature reported in other patients with pathogenic SETD1B mutations.
In a 7-year-old boy (patient 20) with intellectual developmental disorder with seizures and language delay (IDDSELD; 619000), Weerts et al. (2021) identified a de novo heterozygous c.3386C-T transition (c.3386C-T, NM_001353345) in the SETD1B gene, resulting in an ala1129-to-val (A1129V) substitution. The mutation was identified by whole-exome sequencing. The DNA methylation pattern identified in the patient was consistent with the episignature reported in other patients with pathogenic SETD1B mutations.
Den, K., Kato, M., Yamaguchi, T., Miyatake, S., Takata, A., Mizuguchi, T., Miyake, N., Mitsuhashi, S. Matsumoto, N. A novel de novo frameshift variant in SETD1B causes epilepsy. J. Hum. Genet. 64: 821-827, 2019. [PubMed: 31110234] [Full Text: https://doi.org/10.1038/s10038-019-0617-1]
Hiraide, T., Nakashima, M., Yamoto, K., Fukuda, T., Kato, M., Ikeda, H., Sugie, Y., Aoto, K., Kaname, T., Nakabayashi, K., Ogata, T., Matsumoto, N., Saitsu, H. De novo variants in SETD are associated with intellectual disability, epilepsy and autism. Hum. Genet. 137: 95-104, 2018. [PubMed: 29322246] [Full Text: https://doi.org/10.1007/s00439-017-1863-y]
Kikuno, R., Nagase, T., Ishikawa, K., Hirosawa, M., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. XIV. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 6: 197-205, 1999. [PubMed: 10470851] [Full Text: https://doi.org/10.1093/dnares/6.3.197]
Krzyzewska, I. M., Maas, S. M., Hennerman, P., Lip, K., Venema, A., Baranano, K., Chassevent, A., Aref-Eshghi, E., van Essen, A. J., Fukuda, T., Ideda, H., Jacquemont, M., and 15 others. A genome-wide DNA methylation signature for SETD1B-related syndrome. Clin. Epigenet. 11: 156, 2019. Note: Electronic Article. [PubMed: 31685013] [Full Text: https://doi.org/10.1186/s13148-019-0749-3]
Lee, J. H., Tate, C. M., You, J.S., Skalnik, D. G. Identification and characterization of the human Set1B histone H3-Lys4 methyltransferase complex. J. Biol. Chem. 282: 13419-13428, 2007. [PubMed: 17355966] [Full Text: https://doi.org/10.1074/jbc.M609809200]
Li, Y., Han, J., Zhang, Y., Cao, F., Liu, Z., Li, S., Wu, J., Hu, C., Wang, Y., Shuai, J., Chen, J., Cao, L., Li, D., Shi, P., Tian, C., Zhang, J., Dou, Y., Li, G., Chen, Y., Lei, M. Structural basis for activity regulation of MLL family methyltransferases. Nature 530: 447-452, 2016. [PubMed: 26886794] [Full Text: https://doi.org/10.1038/nature16952]
Ortmann, B. M., Burrows, N., Lobb, I. T., Arnaiz, E., Wit, N., Bailey, P. S. J., Jordon, L. H., Lombardi, O., Penalver, A., McCaffrey, J., Seear, R., Mole, D. R., Ratcliffe, P. J., Maxwell, P. H., Nathan, J. A. The HIF complex recruits the histone methyltransferase SET1B to activate specific hypoxia-inducible genes. Nature Genet. 53: 1022-1035, 2021. [PubMed: 34155378] [Full Text: https://doi.org/10.1038/s41588-021-00887-y]
Roston, A., Evans, D., Gill, H., McKinnon, M., Isidor, B., Cogne, B., Mwenifumbo, J., van Karnebeek, C., An, J., Jones, S. J. M., Farrer, M., Demos, M., Connelly, M., Gibson, W. T., CAUSES Study, EPGEN Study. SETD1B-associated neurodevelopmental disorder. J. Med. Genet. 58: 196-204, 2021. Note: Erratum: J. Med. Genet. 17Aug, 2022. Advance Electronic Publication. [PubMed: 32546566] [Full Text: https://doi.org/10.1136/jmedgenet-2019-106756]
Scott, A. F. Personal Communication. Baltimore, Md. 5/9/2007.
Weerts, M. J. A., Lanko, K., Guzman-Vega, F. J., Jackson, A., Ramakrishnan, R., Cardona-Londono, K. J., Pena-Guerra, K. A., van Bever, Y., van Paassen, B. W., Kievit, A., van Slegtenhorst, M., Allen, N. M., and 86 others. Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome. Genet. Med. 23: 2122-2137, 2021. [PubMed: 34345025] [Full Text: https://doi.org/10.1038/s41436-021-01246-2]