Alternative titles; symbols
HGNC Approved Gene Symbol: SETD5
Cytogenetic location: 3p25.3 Genomic coordinates (GRCh38): 3:9,397,615-9,478,154 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p25.3 | Intellectual developmental disorder, autosomal dominant 23 | 615761 | Autosomal dominant | 3 |
By sequencing clones obtained from a size-fractionated human fetal brain cDNA library, Nagase et al. (2000) obtained a partial SETD5 clone, which they designated KIAA1757. RT-PCR ELISA detected highest SETD5 expression in adult brain, followed by spinal cord, most isolated adult brain regions, and ovary. Much lower expression was detected in other adult peripheral tissues and in fetal brain and liver.
The SETD5 gene encodes a 1,442-residue protein that is a putative methyltransferase (summary by Grozeva et al., 2014).
Hartz (2014) mapped the SETD5 gene to chromosome 3p25.3 based on an alignment of the SETD5 sequence (GenBank AB051544) with the genomic sequence (GRCh37).
In 7 unrelated boys with autosomal dominant intellectual developmental disorder-23 (MRD23; 615761), Grozeva et al. (2014) identified 7 different de novo heterozygous truncating or frameshift mutations in the SETD5 gene (see, e.g., 615743.0001-615743.0005), consistent with a loss of function and haploinsufficiency. The patients were ascertained from a larger cohort of 996 individuals with intellectual disability who were screened for mutations in 565 known or candidate genes using a targeted next-generation sequencing approach. All of the mutations were confirmed by Sanger sequencing, and molecular evidence was compatible with de novo occurrence. None were found in the dbSNP, 1000 Genomes Project, or Exome Sequencing Project databases. The patients accounted for 0.7% of the cohort, suggesting that SETD5 mutations may be relatively common causes of impaired intellectual development.
Sessa et al. (2019) noted that Setd5 -/- mice die in utero. They found that Setd5 +/- mice had a 50% reduction in both Setd5 mRNA and protein and were dwarfs compared with wildtype. Setd5 +/- mice showed increased proliferation of cortical progenitor cells, impaired synapse formation in neurons, and cortical tissue defects in brain, leading to social and cognitive behavioral deficits. Setd5 selectively localized on gene bodies, but not on promoters, of highly transcribed genes and acted as a H3K36 lysine methyltransferase to regulate gene transcription, at least in part, by controlling H3K36me3 levels along gene bodies. Setd5 haploinsufficiency affected H3K36me3 levels on neural cell chromatin and slowed transcription elongation and splicing of Setd5 target genes related to brain development and neuronal functions.
In a boy with autosomal dominant intellectual developmental disorder-23 (MRD23; 615761), Grozeva et al. (2014) identified a de novo heterozygous c.1195A-T transversion in the SETD5 gene, resulting in a lys399-to-ter (K399X) substitution.
In a boy with autosomal dominant intellectual developmental disorder-23 (MRD23; 615761), Grozeva et al. (2014) identified a de novo heterozygous 2-bp deletion (c.2177_2178del) in the SETD5 gene, resulting in a frameshift and premature termination (Thr726AsnfsTer39).
In a boy with autosomal dominant intellectual developmental disorder-23 (MRD23; 615761), Grozeva et al. (2014) identified a de novo heterozygous c.3001C-T transition in the SETD5 gene, resulting in an arg1001-to-ter (R1001X) substitution.
In a boy with autosomal dominant intellectual developmental disorder-23 (MRD23; 615761), Grozeva et al. (2014) identified a de novo heterozygous 1-bp duplication (c.3771dupG) in the SETD5 gene, resulting in a frameshift and premature termination (Ser1258GlufsTer65).
In a boy with autosomal dominant intellectual developmental disorder-23 (MRD23; 615761), Grozeva et al. (2014) identified a de novo heterozygous 1-bp deletion (c.3856delT) in the SETD5 gene, resulting in a frameshift and premature termination (Ser1286LeufsTer84).
In a patient with autosomal dominant intellectual developmental disorder-23 (MRD23; 615761), Rauch et al. (2012) identified a de novo heterozygous c.2302C-T transition (c.2302C-T, NM_001080517.1) in the SETD5 gene, resulting in an arg768-to-ter (R768X) substitution. The mutation was predicted to cause nonsense-mediated mRNA decay. The patient was ascertained from a cohort of 51 patients with intellectual disability who underwent exome sequencing. Rauch et al. (2012) postulated haploinsufficiency as the disease mechanism.
In a patient with autosomal dominant intellectual developmental disorder-23 (MRD23; 615761), Kuechler et al. (2015) identified a de novo heterozygous 81-bp intragenic deletion (chr3.9,477,570_9,477,650del, GRCh37) in the SETD5 gene. The deletion, which was found by exome sequencing and confirmed by Sanger sequencing, deleted 7 codons of exon 7 and 60 adjacent basepairs of intron 7. The breakpoint regions constituted a junctional microhomology. In addition, the patient carried a de novo heterozygous c.523A-G transition, resulting in a ser175-to-gly (S175G) substitution that was upstream of the deletion. This substitution was only present on reads that also carried the deletion: any independent effect of the substitution was abolished by nonsense-mediated mRNA decay of the allele due to the deletion, consistent with haploinsufficiency.
Grozeva, D., Carss, K., Spasic-Boskovic, O., Parker, M. J., Archer, H., Firth, H. V., Park, S.-M., Canham, N., Holder, S. E., Wilson, M., Hackett, A., Field, M., Floyd, J. A. B., UK10K Consortium, Hurles, M., Raymond, F. L. De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability. Am. J. Hum. Genet. 94: 618-624, 2014. [PubMed: 24680889] [Full Text: https://doi.org/10.1016/j.ajhg.2014.03.006]
Hartz, P. A. Personal Communication. Baltimore, Md. 4/22/2014.
Kuechler, A., Zink, A. M., Wieland, T., Ludecke, H.-J., Cremer, K., Salviati, L., Magini, P., Najafi, K., Zweier, C., Czeschik, J. C., Aretz, S., Endele, S., and 14 others. Loss-of-function variants of SETD5 cause intellectual disability and the core phenotype of microdeletion 3p25.3 syndrome. Europ. J. Hum. Genet. 23: 753-760, 2015. [PubMed: 25138099] [Full Text: https://doi.org/10.1038/ejhg.2014.165]
Nagase, T., Kikuno, R., Hattori, A., Kondo, Y., Okumura, K., Ohara, O. Prediction of the coding sequences of unidentified human genes, XIX. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 7: 347-355, 2000. [PubMed: 11214970] [Full Text: https://doi.org/10.1093/dnares/7.6.347]
Rauch, A., Wieczorek, D., Graf, E., Wieland, T., Endele, S., Schwarzmayr, T., Albrecht, B., Bartholdi, D., Beygo, J., Di Donato, N., Dufke, A., Cremer, K., and 27 others. Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Lancet 380: 1674-1682, 2012. [PubMed: 23020937] [Full Text: https://doi.org/10.1016/S0140-6736(12)61480-9]
Sessa, A., Fagnocchi, L., Mastrototaro, G., Massimino, L., Zaghi, M., Indrigo, M., Cattaneo, S., Martini, D., Gabellini, C., Pucci, C., Fasciani, A., Belli, R., Taverna, S., Andreazzoli, M., Zippo, A., Broccoli, V. SETD5 regulates chromatin methylation state and preserves global transcriptional fidelity during brain development and neuronal wiring. Neuron 104: 271-289, 2019. [PubMed: 31515109] [Full Text: https://doi.org/10.1016/j.neuron.2019.07.013]