Alternative titles; symbols
HGNC Approved Gene Symbol: SETD2
Cytogenetic location: 3p21.31 Genomic coordinates (GRCh38): 3:47,016,436-47,164,840 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p21.31 | Intellectual developmental disorder, autosomal dominant 70 | 620157 | Autosomal dominant | 3 |
| Luscan-Lumish syndrome | 616831 | Autosomal dominant | 3 | |
| Rabin-Pappas syndrome | 620155 | Autosomal dominant | 3 |
Methylation of histone H3 (see 602810) lys36 (H3K36) is associated with transcribed regions and functions in transcription fidelity, RNA splicing, and DNA repair. SETD2 is the primary methyltransferase catalyzing H3K36 trimethylation (H3K36me3) (summary by Xu et al., 2019)
Huntington disease (143100) is caused by expansion of a CAG trinucleotide repeat encoding an N-terminal polyglutamine region in huntingtin (HTT; 613004) to more than 34 units. Using N-terminal domains of HTT containing 58 or 62 glutamines in a yeast 2-hybrid assay of a fetal brain cDNA library, followed by database analysis and screening brain and testis cDNA libraries, Faber et al. (1998) obtained a partial SETD2 clone, which they called HYPB. The deduced protein has a WW domain. Northern blot analysis detected a transcript of about 9.0 kb that was variably expressed in all tissues examined.
By sequencing clones obtained from a size-fractionated adult brain cDNA library, Nagase et al. (2000) cloned SETD2, which they designated KIAA1732. The deduced protein contains 1,325 amino acids. RT-PCR detected low SETD2 expression in all adult and fetal tissues and specific adult brain regions examined.
Using a yeast 1-hybrid screen of a HeLa cell cDNA library to identify proteins that could bind transcriptional start site-2 (TS2) of the adenovirus E1A gene, followed by RT-PCR of normal human foreskin fibroblasts, Rega et al. (2001) cloned full-length SETD2, which they called HBP231. The deduced 2,061-amino acid protein has a calculated molecular mass of about 231 kD. It has a putative N-terminal tyrosine phosphorylation site, a central SET domain, and a C-terminal WW/WWP domain that is followed by a putative nuclear localization signal. The C-terminal region of HBP231 corresponds to the HYPB sequence. Northern blot analysis detected a 7.5-kb transcript expressed at variable levels in all tissues examined. Western blot analysis of HeLa cells showed that HBP231 had an apparent molecular mass of 231 kD.
By FISH and genomic sequence analysis, Rega et al. (2001) mapped the SETD2 gene to chromosome 3p21.3-p21.2.
Using a yeast 2-hybrid assay, Faber et al. (1998) showed that HYPB interacted with normal and mutant huntingtin in extracts of Huntington disease lymphoblastoid cells. The interaction was mediated by the WW domain region of HYPB and by the N-terminal proline-rich region in huntingtin, and it was enhanced by lengthening the adjacent glutamine tract.
Using electrophoretic mobility shift analysis with nuclear extracts of HeLa cells, Rega et al. (2001) confirmed that endogenous HBP231 bound the TS2 motif of the adenovirus E1A promoter in a sequence-specific manner. HBP231 expression was elevated in human embryonic kidney cells expressing E1A, suggesting that the observed autoactivation of E1A may be achieved by induced HBP231 expression.
Sun et al. (2005) showed that the SET domain and flanking AWS and postSET domains of human HBP231 mediated H3K36-specific histone methyltransferase activity. The isolated low-charged region of HBP231 immediately following the WW domain showed transcriptional activity, although a longer construct did not. A C-terminal fragment of HBP231 containing the AWS, SET, and postSET domains, the low-charged region, and the WW domain associated with hyperphosphorylated RNA polymerase II (see 180660), but not with the unphosphorylated form. Domain analysis revealed that the region C-terminal to the WW domain mediated the interaction of HBP231 with phosphorylated RNA polymerase II. Sun et al. (2005) concluded that HBP231 may coordinate histone methylation and transcriptional regulation.
The yeast histone deacetylase Rpd3 is recruited to promoters and represses transcription initiation. Carrozza et al. (2005) and Keogh et al. (2005) independently showed that the yeast SETD2 ortholog, Set2, is a histone H3K36 methyltransferase associated with a small Rpd3 complex that signals deacetylation of ORFs by Rpd3 and suppresses transcription initiation.
By immunoprecipitation and pull-down analyses, Park et al. (2016) showed that human SETD2 bound directly to alpha-tubulin (see 602529) in vitro through its SET domain to methylate alpha-tubulin at K40. Analysis in mouse embryonic fibroblasts (MEFs) indicated that microtubule methylation occurred during mitosis and cytokinesis, which could be completed through the catalytic activity of Setd2. Mass spectrometric analysis revealed that methylation of alpha-tubulin at K40 by SETD2 also occurred in vivo and identified SETD2 as a dual-function methyltransferase that directly methylated both histones and alpha-tubulin. Moreover, analysis of MEFs from Setd2 -/- mice showed that Setd2 was a mitotic microtubule methyltransferase, as methylation of microtubules was lost in Setd2 -/- MEFs. Setd2 was required for genomic stability and normal mitosis and cytokinesis, as Setd2 -/- MEFs displayed increase in ploidy and polynucleation, as well as elevated defects in mitosis and cytokinesis. Further analysis with human cells showed that loss of alpha-tubulin methylation by SETD2 caused mitotic and cytokinesis defects, confirming SETD2 as a dual-function methyltransferase for both chromatin and the cytoskeleton.
By bioinformatic analysis, Hacker et al. (2016) identified a high degree of structural and sequence homology between human SETD2 and its yeast ortholog, Set2, especially in their SET and SRI domains. Expression of SETD2 with SET domain mutations, which is found in some cancer cells, especially clear-cell renal cell carcinoma, in SETD2-deficient human cells revealed that different mutations differentially destabilized SETD2 and had separate effects on histone H3K36me3. One SET domain mutation, arg1625 to cys (R1625C), resulted in decreased RNA and a shortened protein half-life, and analysis with purified recombinant protein showed that loss of catalytic activity for this mutant was not due to protein misfolding or reduced thermal stability but rather to diminished substrate binding. Likewise, domain-specific mutations in Set2 resulted in different effects on H3K36 methylation status in yeast. However, in contrast with human cells, histone H3K36me2 was indispensable, whereas H3K36me3 was dispensable. Further analysis demonstrated that SETD2-mediated H3K36me3 in human cells was coupled to efficient resolution of double-strand breaks and the DNA damage response.
Using chromatin immunoprecipitation-sequencing analysis, Xu et al. (2019) showed that H3K36me3 correlated with DNA methylation in fully grown mouse oocytes. However, H3K36me3 was mutually exclusive with H3K4me3 and H3K27me3, and global H3K36me3 and H3K27me3 were unaffected in the absence of DNA methylation. Depletion of Setd2 in mouse oocytes resulted in reduced metaphase II oocyte number and sterility of female mice. H3K36me3 was lost in Setd2-deficient oocytes and led to alteration of the global DNA methylation level, redistribution of H3K4me3 and H3K27me3, and a subsequent change in chromatin accessibility. The redistribution of H3K27me3, but not H3K4me3, partially resulted in aberrant gene expression in Setd2-deficient oocytes. Setd2 promoted the establishment of maternal imprints, likely through H3K36me3-mediated recruitment of Dnmt3a (602769)/Dnmt3l (606588) and simultaneous inhibition of H3K4me3. As a result, maternal imprints and ectopic H3K4me3 at imprinting control regions were lost in Setd2-deficient oocytes. The authors found that maternal H3K36me3 was transiently inherited in early embryos after fertilization, just like H3K4me3 and H3K27me3 during early development. The defective maternal epigenome and aberrant gene expression observed in Setd2-deficient oocytes were inherited in 1-cell embryos after fertilization. Consequently, maternal depletion of Setd2 resulted in absence of maternal DNA replication and failure of zygotic genome activation and maternal RNA clearance, leading to 1-cell arrest after implantation and causing lethality of Setd2-deficient embryos. Further investigation demonstrated that both oocyte cytoplasm and chromatin defects contributed to lethality of Setd2-deficient embryos, and that Setd2-dependent patterning of the maternal epigenome was essential for postimplantation development.
Luscan-Lumish syndrome
O'Roak et al. (2012, 2012) sequenced a total of 677 individual exomes from 209 families from the autism spectrum disorder (ASD) Simons Simplex Collection (SSC) and identified 4 individuals with ASD and heterozygous mutations in the SETD2 gene: 2 with nonsense mutations (paternally-inherited C94X and maternally-inherited Q7X), 1 with a de novo I42F missense mutation, and 1 (patient 12565.p1) with a de novo frameshift mutation. Lumish et al. (2015) stated that the patient with the frameshift mutation (612778.0001) also had a history of failure to thrive, nonfebrile seizures starting at 4 years of age, motor delays, low-normal nonverbal IQ, and macrocephaly, termed Luscan-Lumish syndrome (LLS; 616831).
Iossifov et al. (2014) sequenced exomes from more than 2,500 simplex families, each having a child with ASD, and identified 2 unrelated individuals with mutations in the SETD2 gene, a 1-basepair deletion and a missense variant. Most of the families were from the ASD SSC.
In 2 'Sotos syndrome-like' patients, Luscan et al. (2014) identified heterozygous mutations in the SETD2 gene (612778.0002 and 612778.0003). Neither variant was reported in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases.
By whole-exome sequencing in a 17-year-old girl with Luscan-Lumish syndrome, Lumish et al. (2015) identified a heterozygous de novo frameshift mutation (612778.0004) in the SETD2 gene. The mutation was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project database, in the dbSNP database, or in over 9,000 clinical exomes sequenced at GeneDx.
In 2 patients with intellectual disability, speech delay, autism spectrum disorder, and macrocephaly consistent with Luscan-Lumish syndrome, van Rij et al. (2018) identified de novo heterozygous frameshift mutations in the SETD2 gene (NM_014159.6). These included a deletion/insertion (c.1647_1667delinsAC) in exon 3 and a single base-pair deletion (c.6775delG) in exon 15, both resulting in a frameshift and a premature stop codon. The variants were not present in the unaffected parents of either patient.
In 4 patients with Luscan-Lumish syndrome, Marzin et al. (2019) identified 2 nonsense mutations (K1426X and Y2157X) and 2 missense mutations (Y1666C and R1625H) in the SETD2 gene (NM_014159.6), all of which were located in the catalytic domain SET2. In a review of their 4 patients and 9 previously reported patients with LLS, the authors found that the mutations were intragenic loss-of-function variants (69% truncating and 31% missense) distributed throughout the gene.
Using targeting sequencing in 2 patients with autism spectrum disorder and other features of Luscan-Lumish syndrome, Chen et al. (2021) identified 2 de novo mutations in the SETD2 gene (NM_014159): a splicing mutation (c.4715+1G-A) and a missense mutation (c.3185C-T, P1062L). Neither variant was reported in large public databases. The authors also evaluated 17 reported de novo SETD2 variants (8 frameshift, 1 nonsense, 7 missense, 1 in-frame deletion). All missense variants occurred at residues that were evolutionarily conserved. Using ACMG criteria, 13 of the 19 variants were classified as pathogenic, 5 as likely pathogenic, and one (missense) as a variant of uncertain significance.
Rabin-Pappas Syndrome
In 12 unrelated patients (group 1) with Rabin-Pappas syndrome (RAPAS; 620155), Rabin et al. (2020) identified a de novo heterozygous missense mutation in the SETD2 gene (R1740W; 612778.0005). The mutation, which was found through clinical genetics services, was not present in the gnomAD database. The patients were ascertained through collaborative efforts, and the phenotype determined retrospectively. Functional studies of the variant and studies of patient cells were not performed. The patients had a severe phenotype with intellectual disability, inability to walk or speak, and involvement of multiple organ systems, which was considered to be different from that of patients with other mutations in SETD2 gene, including those with a different mutation at the same codon (R1740Q; 612778.0006).
Intellectual Developmental Disorder 70, Autosomal Dominant
In 3 unrelated patients (group 2) with autosomal dominant intellectual developmental disorder-70 (MRD70; 620157), Rabin et al. (2020) identified a de novo heterozygous missense mutation in the SETD2 gene (R1740Q; 612778.0006). The mutation, which was found through clinical genetics services, was not present in the gnomAD database. The patients were ascertained through collaborative efforts, and the phenotype determined retrospectively. Functional studies of the variant and studies of patient cells were not performed. The patients had developmental delay with moderately impaired intellectual development, low-normal head circumference, variable and mild dysmorphic features, and absence of additional congenital anomalies or systemic involvement. The phenotype was considered to be different from that of patients with other mutations in the SETD2 gene, including those with a different mutation at the same codon (R1740W; 612778.0005).
By exome sequencing of patients from the Simons Simplex Collection, O'Roak et al. (2012) identified a de novo heterozygous 1-bp deletion (c.6341delA, NM_014159) in the SETD2 gene, resulting in a frameshift (Asn2114IlefsTer33) in a female (patient 12565.p1) with autism spectrum disorder. Lumish et al. (2015) stated that this patient also had failure to thrive, seizures, motor delay, low-normal IQ, and macrocephaly (Luscan-Lumish syndrome, 616831).
In a 26-year-old French man with Luscan-Lumish syndrome (LLS; 616831), who was diagnosed with a 'Sotos-like syndrome,' Luscan et al. (2014) identified a de novo heterozygous c.5444T-G transversion (c.5444T-G, NM_014159.6) in the SETD2 gene, resulting in a leu1815-to-trp (L1815W) substitution at a conserved residue. The mutation was not found in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases.
In a 23-year-old woman with Luscan-Lumish syndrome (LLS; 616831), who was diagnosed with 'Sotos-like syndrome,' Luscan et al. (2014) identified a heterozygous c.820C-T transition (c.820C-T, NM_014159.6), resulting in a gln274-to-ter (Q274X) substitution. The woman was adopted and her biologic parents could not be tested. The mutation was not found in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases.
By whole-exome sequencing in a 17-year-old girl with Luscan-Lumish syndrome (LLS; 616831), Lumish et al. (2015) identified a heterozygous de novo 1-bp deletion (c.2028delT, NM_014159.6) in the SETD2 gene, resulting in a frameshift (Pro677LeufsTer19). This mutations was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project database, in the dbSNP database, or in over 9,000 clinical exomes sequenced at GeneDx.
In 12 unrelated patients (group 1) with Rabin-Pappas syndrome (RAPAS; 620155), Rabin et al. (2020) identified a de novo heterozygous c.5218C-T transition (c.5218C-T, NM_014159.6) in the SETD2 gene, resulting in an arg1740-to-trp (R1740W) substitution at conserved residue in a region of unknown function. The mutation, which was found through clinical genetics services, was not present in the gnomAD database. The patients were ascertained through collaborative efforts, and the phenotype determined retrospectively. Functional studies of the variant and studies of patient cells were not performed. The patients had a severe phenotype with intellectual disability, inability to walk or speak, and involvement of multiple organ systems, which was considered to be different from that of patients with other SETD2 mutations.
In 3 unrelated patients (group 2) with autosomal dominant intellectual developmental disorder-70 (MRD70; 620157), Rabin et al. (2020) identified a de novo heterozygous c.5219G-A transition (c.5219G-A, NM_014159.6) in the SETD2 gene, resulting in an arg1740-to-gln (R1740Q) substitution at a conserved residue in a region of unknown function. The mutation, which was found through clinical genetics services, was not present in the gnomAD database. The patients were ascertained through collaborative efforts, and the phenotype determined retrospectively. Functional studies of the variant and studies of patient cells were not performed. The patients had developmental delay with moderately impaired intellectual development, low-normal head circumference, variable and mild dysmorphic features, and absence of additional congenital anomalies or systemic involvement. The phenotype was considered to be different from that of patients with other mutations in the SETD2 gene.
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