Alternative titles; symbols
HGNC Approved Gene Symbol: KMT5B
Cytogenetic location: 11q13.2 Genomic coordinates (GRCh38): 11:68,154,863-68,213,648 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q13.2 | Intellectual developmental disorder, autosomal dominant 51 | 617788 | Autosomal dominant | 3 |
SUV420H1 and the related enzyme SUV420H2 (613198) function as histone methyltransferases that specifically trimethylate nucleosomal histone H4 (see 602822) on lysine 20 (K20) (Schotta et al., 2004).
By sequencing the IDDM4 (600319) region of chromosome 11, followed by database analysis, Twells et al. (2001) cloned SUV420H1, which they called CGI85. The deduced protein contains 384 amino acids.
Schotta et al. (2004) cloned mouse Suv420h1. The deduced 876-amino acid protein contains an N-terminal SET domain and 3 additional regions that are conserved in Suv420h orthologs from other species. Fluorescence-tagged Suv420h1 localized to pericentric heterochromatin in transfected mouse embryonic fibroblasts (MEFs).
Using RNA interference, Schotta et al. (2004) showed that Suv420h1 and Suv420h2 were required for pericentric accumulation of trimethylated histone H4K20 in MEFs. Accumulation of trimethylated H3K9 (see 602810) was unaffected. The isolated SET domains of Suv420h1 and Suv420h2 showed strong methyltransferase activity toward nucleosomes, but only weak activity toward recombinant histone octamers, and none toward peptides and free histones. Western blot analysis using antibodies directed against mono-, di-, and trimethylated H4K20 showed that Suv420h1 and Suv420h2 products were enriched for trimethylated H4K20.
Twells et al. (2001) determined that the SUV420H1 gene contains at least 10 exons spanning 24 kb.
By analysis of BAC and PAC clones, Twells et al. (2001) mapped the SUV420H1 gene to chromosome 11q13.
In 7 unrelated patients with autosomal dominant intellectual developmental disorder-51 (MRD51; 617788), Iossifov et al. (2014) and Stessman et al. (2017) identified 7 different heterozygous variants in the KMT5B gene (see, e.g., 610881.0001-610881.0003). Four of the variants were categorized as 'likely gene disruptive' (LGD) events, such as nonsense or frameshift variants, and 3 were missense variants predicted to be deleterious. Five of the variants were demonstrated to have occurred de novo. One missense variant was maternally inherited without clinical information on the mother, and parental DNA was not available from another patient to determine segregation. Three of the variants were private, only identified in the affected patient (family), and 4 were classified as 'ultra-rare.' Functional studies of the variants and studies of patient cells were not performed. The patients were ascertained from a large cohort of over 11,730 patients with autism spectrum disorder, intellectual disability, and/or developmental delay involving 15 centers across 7 countries and 4 continents. The authors used single-molecule molecular inversion probes (smMIPs) to sequence 208 candidate genes in these patient samples and confirmed the findings by Sanger sequencing. The findings of LGD and missense mutations in the KMT5B gene was statistically significant. Three of the patients (patients 5, 6, and 7) had previously been reported by Iossifov et al. (2014) as part of a large genetic study on autism.
In 2 unrelated patients with MRD51, Faundes et al. (2018) identified de novo heterozygous loss-of-function variants in the KMT5B gene (610881.0004 and 610881.0005). The patients were ascertained from a cohort of 4,293 trios from the Deciphering Developmental Disorders (DDD) study who underwent exome sequencing. The KMT5B gene was chosen for study through a pathway-based approach focusing on candidate genes involved in histone lysine methylation/demethylation. The variants were filtered against several large databases, including ExAC, the 1000 Genomes Project, and the Exome Sequencing Project. Functional studies of the variants and studies of patient cells were not performed, but both variants were predicted to result in a loss of function and haploinsufficiency. Two additional unrelated patients with a similar phenotype were found to carry de novo heterozygous deletions (399 kb and 839 kb, respectively) encompassing the KMT5B gene.
In a 10-year-old Swedish girl (patient 2, 2135-09D) with autosomal dominant intellectual developmental disorder-51 (MRD51; 617788), Stessman et al. (2017) identified a de novo heterozygous 1-bp deletion (c.725del, NM_017635.4) in the KMT5B gene, resulting in a frameshift and premature termination (Leu242HisfsTer30). The mutation was found by candidate gene sequencing and confirmed by Sanger sequencing; it was considered to be a private mutation, only occurring in this patient. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function.
In a 7-year-old Swedish boy (patient 3, 1895-11D) with autosomal dominant intellectual developmental disorder-51 (MRD51; 617788), Stessman et al. (2017) identified a de novo heterozygous 2-bp deletion (c.1557_1558del, NM_017635.4) in the KMT5B gene, resulting in a frameshift and premature termination (Asn520SerfsTer33). The mutation was found by candidate gene sequencing and confirmed by Sanger sequencing; it was considered to be a private mutation, only occurring in this patient. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function.
In a 14-year-old boy (patient 5, SSC_11519.p1) with autosomal dominant intellectual developmental disorder-51 (MRD51; 617788), Stessman et al. (2017) reported a de novo heterozygous c.791G-C transversion (c.791G-C, NM_017635.4) in the KMT5B gene, resulting in a trp264-to-ser (W264S) substitution. The mutation was found by candidate gene sequencing and confirmed by Sanger sequencing; it was considered to be an 'ultra-rare' mutation. Functional studies of the variant and studies of patient cells were not performed. The patient had previously been reported by Iossifov et al. (2014) as part of a large genetic study on autism in which no clinical details were provided.
In a 13-year-old girl with autosomal dominant intellectual developmental disorder-51 (MRD51; 617788), Faundes et al. (2018) identified a de novo heterozygous 1-bp deletion (c.219delC, NM_017635.4) in the KMT5B gene, predicted to result in a frameshift and premature termination (Ala74ProfsTer10). 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 a loss of function and haploinsufficiency.
In a 19-year-old man with autosomal dominant intellectual developmental disorder-51 (MRD51; 617788), Faundes et al. (2018) identified a de novo heterozygous c.559C-T transition (c.559C-T, NM_017635.4) in the KMT5B gene, resulting in an arg187-to-ter (R187X) 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 a loss of function and haploinsufficiency.
Faundes, V., Newman, W. G., Bernardini, L., Canham, N., Clayton-Smith, J., Dallapiccola, B., Davies, S. J., Demos, M. K., Goldman, A., Gill, H., Horton, R., Kerr, B., and 11 others. Histone lysine methylases and demethylases in the landscape of human developmental disorders. Am. J. Hum. Genet. 102: 175-187, 2018. [PubMed: 29276005] [Full Text: https://doi.org/10.1016/j.ajhg.2017.11.013]
Iossifov, I., O'Roak, B. J., Sanders, S. J., Ronemus, M., Krumm, N., Levy, D., Stessman, H. A., Witherspoon, K. T., Vives, L., Patterson, K. E., Smith, J. D., Paeper, B., and 35 others. The contribution of de novo coding mutations to autism spectrum disorder. Nature 515: 216-221, 2014. [PubMed: 25363768] [Full Text: https://doi.org/10.1038/nature13908]
Schotta, G., Lachner, M., Sarma, K., Ebert, A., Sengupta, R., Reuter, G., Reinberg, D., Jenuwein, T. A silencing pathway to induce H3-K9 and H4-K20 trimethylation at constitutive heterochromatin. Genes Dev. 18: 1251-1262, 2004. [PubMed: 15145825] [Full Text: https://doi.org/10.1101/gad.300704]
Stessman, H. A. F., Xiong, B., Coe, B. P., Wang, T., Hoekzema, K., Fenckova, M., Kvarnung, M., Gerdts, J., Trinh, S., Cosemans, N., Vives, L., Lin, J., and 41 others. Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases. Nature Genet. 49: 515-526, 2017. [PubMed: 28191889] [Full Text: https://doi.org/10.1038/ng.3792]
Twells, R. C. J., Metzker, M. L., Brown, S. D., Cox, R., Garey, C., Hammond, H., Hey, P. J., Levy, E., Nakagawa, Y., Philips, M. S., Todd, J. A., Hess, J. F. The sequence and gene characterization of a 400-kb candidate region for IDDM4 on chromosome 11q13. Genomics 72: 231-242, 2001. [PubMed: 11401438] [Full Text: https://doi.org/10.1006/geno.2000.6492]