Alternative titles; symbols
HGNC Approved Gene Symbol: SETD1A
Cytogenetic location: 16p11.2 Genomic coordinates (GRCh38): 16:30,957,754-30,984,664 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16p11.2 | Epilepsy, early-onset, 2, with or without developmental delay | 618832 | Autosomal dominant | 3 |
| Neurodevelopmental disorder with speech impairment and dysmorphic facies | 619056 | Autosomal dominant | 3 |
SET1A is a component of a histone methyltransferase (HMT) complex that produces mono-, di-, and trimethylated histone H3 at lys4 (K4). The complex is the analog of the S. cerevisiae Set1/COMPASS complex (Lee and Skalnik, 2005). Also see SET1B (611055).
Wysocka et al. (2003) purified proteins associated with HCF1 (300019) and identified a previously uncharacterized human trithorax (159555)-related SET1/ASH2 (604782) histone methyltransferase complex that included SET1A, the human homolog of S. cerevisiae Set1. The SET1A protein contains 1,709 amino acids and, like yeast Set1, contains highly conserved SET and post-SET domains at the C terminus that are related to those of the human and Drosophila trithorax protein, as well as an N-terminal region with similarity to the RRM RNA recognition motif found in many RNA-binding proteins. Consistent with the presence of HCF1 in animals but not yeast, the human and C. elegans, but not the yeast, Set1 proteins contain an HCF1-binding motif found in HCF1 Kelch domain-binding proteins such as the transcriptional activator VP16.
Yu et al. (2019) found expression of the Setd1a gene in the developing mouse brain.
By database analysis, Mukai et al. (2019) found that Setd1a was expressed throughout adult mouse brain, with higher expression in neocortex. Real-time quantitative RT-PCR detected Setd1a mRNA at various developmental stages in mouse prefrontal cortex (PFC). Immunostaining analysis of the prelimbic area in medial PFC of 6-week-old mice revealed Setd1a-positive cells distributed in all cortical layers except L1 and merged with neuronal nuclei cells.
By radiation hybrid analysis, Nagase et al. (1997) mapped the SETD1A gene, which they designated KIAA0339, to chromosome 16. Scott (2007) mapped the gene to 16p11.2 based on an alignment of the SETD1A sequence (GenBank AB002337) with the genomic sequence (build 36.2).
Wysocka et al. (2003) showed that, as in yeast, the HCF1-associated human SET1/ASH2 HMT complex possesses histone H3-K4 methylation activity, which activates transcription. Furthermore, this activity is blocked by premethylation of K9, a repressor of transcription, indicating that there is crosstalk between K9 methylation and K4 methylation by the SET1/ASH2 complex. The human SET1/ASH2 HMT complex associates with the HCF1 Kelch domain, whereas Sin3 histone deacetylase (HDAC) (see 607776 and 601241), a chromatin-associated complex which represses transcription, associates with the basic region. From subsequent cosedimentation and immunoprecipitation experiments, Wysocka et al. (2003) found that the human SET1/ASH2 complex, in mutually exclusive interactions, can associate with HCF1 bound to Sin3 HDAC or to HCF1 bound to VP16, indicating a diversity of transcriptional regulatory roles.
Lee and Skalnik (2005) determined that SET1A associates with an approximately 450-kD complex that contains 5 noncatalytic components including ASH2, CXXC1 (609150), RBBP5 (600697), WDR5 (609012), and WDR82 (611059). By confocal microscopy, they demonstrated that SET1A and CXXC1 colocalize to nuclear speckles associated with euchromatin.
Using a short hairpin RNA screen targeting 43 histone lysine methyltransferases (KMTs), Tajima et al. (2015) showed that the KMT SETD1A suppressed expression of the antiproliferative gene BTG2 (601597) by inducing several BTG2-targeting microRNAs. Although the mechanism was indirect, it was a highly specific way by which a chromatin regulator that mediates transcriptional activating marks could induce downregulation of a critical effector gene. Moreover, the mechanism was shared with multiple genes of the p53 pathway. Tajima et al. (2015) concluded that SETD1A has an important role in regulating tumor growth.
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; SET1B, 611055). 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.
Hoshii et al. (2018) found that knockdown of Setd1a in MLLAF9 mouse leukemia cells induced apoptosis, cell cycle arrest, and neutrophilic differentiation, indicating that Setd1a was required for leukemia cell growth and survival. Setd1a was required to regulate expression of genes important for the DNA damage response, thereby protecting leukemia cell chromosomal integrity and preventing p53 (TP53; 191170)-dependent apoptosis. Mutation analysis showed that an internal region of Setd1a, which the authors termed FLOS1, was required for maintenance of genes important for the DNA damage response. Setd1a was crucial for chromosomal recruitment of cyclin K (CCNK; 603544), and the FLOS1 domain of Setd1a bound cyclin K. The Setd1a-cyclin K pathway promoted Cdk12 (615514) occupancy/activation, phosphorylation of RNA polymerase II (see 180660), and expression of DNA damage response genes during S-phase of the cell cycle. Furthermore, the authors confirmed that the SETD1A/cyclin K/CDK12 pathway also regulated growth in human leukemia cells.
Higgs et al. (2018) found that SETD1A and BOD1L (BOD1L1; 616746) interacted to regulate genome stability following replication stress in HeLa cells. SETD1A and BOD1L acted together to stabilize RAD51 (179617) on nascent DNA by restraining the antirecombinase functions of BLM (RECQL3; 604610)/FBH1 (FBXO18; 607222), thereby protecting damaged replication forks from DNA2 (601810)-dependent resection. Knockdown analysis showed that the catalytic methyltransferase activity of SETD1A was required for its role in fork protection. SETD1A-catalyzed H3K4 methylation on nascent DNA was also required for fork protection. H3K4 methylation protected genome stability by suppressing fork degradation mediated by CHD4 (603277). SETD1A-dependent H3K4 methylation also enhanced downstream FANCD2 (613984)-dependent histone chaperone activity, allowing SETD1A, H3K4 methylation, and FANCD2 to function within the same pathway to promote RAD51-dependent fork protection.
Early-Onset Epilepsy with or without Developmental Delay
In 3 members of a 4-generation Chinese family with early-onset epilepsy without developmental delay (EPEO2; 618832), Yu et al. (2019) identified a heterozygous missense mutation in the SETD1A gene (R913C; 611052.0002). Three additional patients with a similar disorder, with or without developmental delay, were subsequently found to carry de novo heterozygous missense mutations in the SETD1A gene (Q269R, 611052.0003; G1369R, 611052.0004; and R1392H, 611052.0005). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in 1 family. Studies of patient cells were not performed. Expression of wildtype SETD1A and constructs of the 4 mutations into mouse cortical primary neurons showed that the mutations were associated with decreased density of mushroom-like spines on the secondary branches of dendrites, which represent excitatory synapses. In contrast, the mutations had no effect on axon length. The findings suggested that the SETD1A mutations do not affect axon growth or general neuronal morphology, whereas they may have an adverse effect on the normal development of synapses. Studies in mouse brain also suggested that the mutations disrupt normal neuronal development, which may lead to epilepsy (see ANIMAL MODEL).
Neurodevelopmental Disorder With Speech Impairment And Dysmorphic Facies
In 15 unrelated patients with neurodevelopmental disorder with speech impairment and dysmorphic facies (NEDSID; 619056), Kummeling et al. (2021) identified 14 different de novo heterozygous mutations in the SETD1A gene (see, e.g., 611052.0001; 611052.0006-611052.0008). The mutations were found by routine diagnostic testing and the patients were ascertained from several different places through the GeneMatcher program. There were 5 nonsense, 6 frameshift, 1 missense, and 2 splice site mutations. All variants were predicted to disrupt or delete the SET catalytic domain. Five patients carried additional variants of uncertain significance affecting other genes. Analysis of fibroblasts derived from 3 patients, including the patient with the only SETD1A missense variant (Y1499D; 611052.0006), showed elevated activation of the DNA damage response and increased DNA degradation under stress conditions compared to controls. The findings were consistent with a loss-of-function effect and SETD1A haploinsufficiency. Kummeling et al. (2021) concluded that the findings were consistent with a possible role of H3K4 methylation and other epigenetic changes in regulating the function of adult neurons post development.
Association with Schizophrenia
Using exome data from 231 case trios with schizophrenia (181500) and 34 control trios, Takata et al. (2014) identified 2 de novo heterozygous loss-of-function variants in the SETD1A gene (see, e.g., 611052.0001) in 2 unrelated patients with schizophrenia. The patients also had learning difficulties and obsessive-compulsive disorder. The findings suggested that dysfunction of a gene involved in chromatin regulation may predispose to the development of schizophrenia.
Using exome data from a cohort of 1,021 patients with schizophrenia, Takata et al. (2016) identified a patient who carried a de novo heterozygous, potentially functional synonymous variant in the SETD1A gene. These findings were significant compared to controls (p = 1.79 x 10(-6), p corrected = 0.033). Functional studies of the variants and studies of patient cells were not performed. Takata et al. (2016) noted that Guipponi et al. (2014) had identified a patient with schizophrenia who had the same loss-of-function variant in the SET1A gene that had been identified in the 2 patients with schizophrenia reported by Takata et al. (2014). They stated that, in total, 3 de novo loss-of-function mutations and 1 de novo functional synonymous mutation had been found in the SET1A gene among 1,074 probands (p = 1.2 x 10 (-8)).
By exome sequencing of 4,264 patients with schizophrenia, 9,343 controls, and 1,077 trios, Singh et al. (2016) identified 1 de novo and 6 case loss-of-function variants in the SETD1A gene (see, e.g., 611052.0001). No loss-of-function variants were found in controls (p = 3.3 x 10 (-9)). Including 3 previously reported patients (Takata et al., 2014; Guipponi et al., 2014), 7 of 10 individuals with schizophrenia who carried SETD1A variants also had learning difficulties. Metaanalysis results showed that SETD1A disruptions are rare in schizophrenia, occurring in about 0.13% of cases. Singh et al. (2016) also found heterozygous loss-of-function variants in the SETD1A gene in 4 of 4,281 children with severe neurodevelopmental disorders and in 2 individuals from a sample of 5,720 Finnish exomes, both of whom had neuropsychiatric phenotypes. The findings suggested that loss-of-function variants in the SETD1A gene can cause a range of neurodevelopmental disorders, and that epigenetic dysregulation of the histone H3K4 methylation pathway may play a role in the pathogenesis of schizophrenia.
Tusi et al. (2015) found that Setd1a -/- mice were embryonic lethal. Conditional knockout of Setd1a in the hematopoietic compartment resulted in blockage of progenitor-to-precursor B-cell development in bone marrow and B-cell maturation in spleen. Conditional knockout mice exhibited an enlarged spleen with disrupted splenic architecture and leukocytopenia. Lack of Setd1a in bone marrow reduced the level of H3K4 trimethylation at critical B-cell gene loci, including Pax5 (167414), Rag1 (179615), and Rag2 (179616), which are important for IgH locus (147100) contractions and rearrangement. Tusi et al. (2015) concluded that SETD1A and the epigenetic modifications it mediates are critical in regulating IgH rearrangement and B-cell development.
Yu et al. (2019) used electroporation to introduce the R913C SETD1A mutation into E14.5 mouse fetuses. Postmortem examination indicated that neurons expressing the R913C mutation migrated faster than controls, suggesting that the mutation disturbs the normal process of cortical development. Transcriptome analysis of cortical neuron samples from fetal mice transfected with wildtype SETD1A or with the R913C, Q269R, G1369R, or R1392H mutations showed that the G1369R and R1392H mutations were associated with significant downregulation of Neurl4 (615865) and Usp39 (611594) compared to controls. Changes in Neurl4 expression due to R913C and Q269R did not reach statistical significance. In contrast, shRNA knockdown of the mouse Setd1a gene resulted in increased expression levels of Neurl4 and Usp39. Both of these genes are associated with the ubiquitin ligase pathway.
Mukai et al. (2019) found that Setd1a +/- mice had approximately 50% reduction of Setd1a RNA and protein levels but were indistinguishable from wildtype mice in terms of body size, weight, and posture. Brains of adult Setd1a +/- mice manifested normal gross morphology with only modestly diminished overall density of neurons. However, Setd1a deficiency impaired working memory and altered neuronal short-term plasticity and excitability in PFC. Examination of laminar organization and cytoarchitecture in cortex of Setd1a +/- mice showed that Setd1a deficiency disrupted axonal branching and spine density. Identification of direct targets of Setd1a in PFC of adult mice revealed that Setd1a bound both promoters and enhancers of its target genes with an overlap of Setd1a and Mef2 on enhancers. Setd1a targets were highly expressed in pyramidal neurons and displayed a complex pattern of transcriptional dysregulation shaped by the presumed opposing functions of Setd1a on promoters and Mef2-bound enhancers. In addition, genes regulated by Setd1a played distinct roles in both prenatal and postnatal neurodevelopment and were associated with schizophrenia and other neurodevelopmental disorders. Restoration of Setd1a or pharmacologic inhibition of Lsd1 (KDM1A; 609132) rescued working memory deficits in adult Setd1a-deficient mice and counteracted the effects of Setd1a deficiency.
Nagahama et al. (2020) generated heterozygous mice carrying a frameshift mutation in exon 7 of the Setd1a gene (Setd1a +/-), mimicking a loss-of-function mutation in patients with schizophrenia (Singh et al., 2016; Takata et al., 2014). Setd1a protein expression was almost half in medial prefrontal cortex (mPFC) of Setd1a +/- mice compared with wildtype, and the birth rate of Setd1a +/- pups was also lower. Setd1a +/- mice displayed various abnormal behaviors relevant to schizophrenia. Setd1a +/- mice also exhibited attenuated excitatory synaptic transmission in layer 2/3 (L2/3) pyramidal neurons of the mPFC, inducing an imbalance of excitation and inhibition of L2/3 neurons of the mPFC. Expression of genes associated with neurodevelopmental disorders and genes related to presynaptic and postsynaptic functions was altered in the mPFC of Setd1a +/- mice. Likewise, Setd1a knockdown specifically in L2/3 pyramidal neurons of the mPFC attenuated both presynaptic and postsynaptic functions in L2/3 pyramidal neurons, leading to elevation of excitation and inhibition balance of synaptic inputs and recapitulating impaired social behavior displayed by Setd1a +/- mice. However, Setd1a at the postsynaptic site, but not in presynaptic neurons, was required for maintaining excitatory synaptic function and structure in L2/3 pyramidal neurons of the mPFC.
Kummeling et al. (2021) found that knockdown of the Drosophila SETD1A ortholog Set1 in terminally differentiated postmitotic neurons of the mushroom body (MB), the primary memory and learning center of the fly brain, resulted in memory deficits as assessed by the courtship conditioning assay. Histologic studies of mutant fly brains did not show morphologic abnormalities in the MB. The authors concluded that this gene is required for normal functioning of adult MB neurons during memory formation, rather than during development.
In 2 unrelated patients (patients 14 and 15) with neurodevelopmental disorder with speech impairment and dysmorphic facies (NEDSID; 619056), Kummeling et al. (2021) identified a de novo heterozygous 2-bp deletion (c.4582-2_4582-1delAG) in intron 15 of the SETD1A gene, resulting in a splice site alteration. The mutation was found by routine diagnostic testing: it was present at a low level in the heterozygous state in the gnomAD database (8.237 x 10(-6)). RT-PCR analysis of patient cells indicated that the mutation resulted in a splicing defect between exons 15 and 16, which would interrupt the functional N-SET domain. The mutant transcript was partially subject to nonsense-mediated mRNA decay. Immunoblot analysis of patient cells showed decreased levels of the SETD1A protein compared to controls. Under stress conditions, patient cells showed elevated activation of the DNA damage response and increased DNA degradation compared to controls. The overall findings were consistent with a loss-of-function effect and SETD1A haploinsufficiency. Both patients had behavioral abnormalities, including 1 with features of bipolar disorder.
In 2 unrelated patients with schizophrenia, Singh et al. (2016) identified a heterozygous 2-bp deletion (c.4582-2_4582-1delAG) in intron 15 of the SETD1A gene, resulting in a splice site alteration and a predicted premature stop codon. The patients also had learning difficulties and obsessive-compulsive disorder. Singh et al. (2016) noted that previous studies (Takata et al., 2014; Guipponi et al., 2014) had also found an association between this variant and schizophrenia in 3 other unrelated patients. Singh et al. (2016) also found heterozygosity for this variant in 3 of 4,281 children with severe neurodevelopmental disorders: 2 occurred de novo and 1 was maternally inherited.
In 3 members of a 4-generation Chinese family with early-onset epilepsy without developmental delay (EPEO2; 618832), Yu et al. (2019) identified a heterozygous c.2737C-T transition in exon 10 of the SETD1A gene, resulting in an arg913-to-cys (R913C) substitution in a region far from the SET domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the dbSNP, 1000 Genomes Project, ExAC, or gnomAD databases. Although studies of patient cells were not performed, expression studies in mouse primary neurons and studies of mice carrying the mutation suggested that it may disrupt normal neuronal and synaptic development.
In a 2.5-year-old Chinese girl (patient 2) with early-onset epilepsy without developmental delay (EPEO2; 618832), Yu et al. (2019) identified a de novo heterozygous c.806A-G transition in exon 6 of the SETD1A gene, resulting in a gln269-to-arg (Q269R) substitution in a region far from the SET domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP, 1000 Genomes Project, ExAC, or gnomAD databases. Although studies of patient cells were not performed, expression studies in mouse primary neurons and studies of mice carrying the mutation suggested that it may disrupt normal neuronal and synaptic development.
In a 2-year-old Chinese boy (patient 3) with early-onset epilepsy with developmental delay (EPEO2; 618832), Yu et al. (2019) identified a de novo heterozygous c.4105G-A transition in exon 14 of the SETD1A gene, resulting in a gly1369-to-arg (G1369R) substitution in a region close to the SET domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP, 1000 Genomes Project, or ExAC databases, but was found at a low frequency (7.9 x 10(-6)) in the gnomAD database. The variant was not found in East Asians. Although studies of patient cells were not performed, expression studies in mouse primary neurons and studies of mice carrying the mutation suggested that it may disrupt normal neuronal and synaptic development.
In a Chinese boy (patient 4) with early-onset epilepsy with presumed developmental delay (EPEO2; 618832), Yu et al. (2019) identified a de novo heterozygous c.4175G-A transition in exon 14 of the SETD1A gene, resulting in an arg1392-to-his (R1392H) substitution in a region close to the SET domain. The mutation, which was confirmed by Sanger sequencing, was not found in the dbSNP and 1000 Genomes Project databases, but was found at low frequencies in the ExAC (1.0 x 10(-4)) and gnomAD (3.3 x 10(-5)) databases. The variant was not found in East Asians. Although studies of patient cells were not performed, expression studies in mouse primary neurons and studies of mice carrying the mutation suggested that it may disrupt normal neuronal and synaptic development.
In a 4.7-year-old boy (patient 13) with neurodevelopmental disorder with speech impairment and dysmorphic facies (NEDSID; 619056), Kummeling et al. (2021) identified a de novo heterozygous c.4495T-G transversion (c.4495T-G, NM_014712.2) in the SETD1A gene, resulting in a tyr1499-to-asp (Y1499D) substitution within the catalytic SET domain. The mutation was found by routine diagnostic testing. Analysis of patient cells showed normal SETD1A protein levels. However, under stress conditions, patient cells showed elevated activation of the DNA damage response and increased DNA degradation compared to controls. The findings were consistent with a loss-of-function effect and SETD1A haploinsufficiency. The patient also carried variants of unknown significance in 2 other genes (EFNB2, 600527 and NHS, 300457).
In a 10.4-year-old girl (patient 6) with neurodevelopmental disorder with speech impairment and dysmorphic facies (NEDSID; 619056), Kummeling et al. (2021) identified a de novo heterozygous 2-bp deletion (c.1602_1603del, NM_014712.2) in the SETD1A gene, resulting in a frameshift and premature termination (Gly535AlafsTer12) before the catalytic domain. The mutation was found by routine diagnostic testing. Immunoblot analysis of patient cells showed decreased levels of the SETD1A protein compared to controls. Under stress conditions, patient cell showed elevated activation of the DNA damage response and increased DNA degradation compared to controls. The findings were consistent with a loss-of-function effect and SETD1A haploinsufficiency.
In a 6-year-old girl (patient 2) with neurodevelopmental disorder with speech impairment and dysmorphic facies (NEDSID; 619056), Kummeling et al. (2021) identified a de novo heterozygous 1-bp duplication (c.1014dupC, NM_014712.2) in the SETD1A gene, resulting in a frameshift and premature termination (Ala339ArgfsTer23) before the catalytic domain. The mutation was found by routine diagnostic testing. Functional studies of the variant and studies of patient cells were not performed, but the authors postulated a loss-of-function effect with haploinsufficiency.
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