A de novo LoF variant in the KMT2C gene was identified in an ASD proband from the Simon Simplex Collection (PMIDs 22495309), while a second de novo LoF variant in this gene was identified in one ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified KMT2C as a gene meeting high statistical significance with a 0.01 < FDR 0.05, meaning that this gene had a 95% chance of being a true autism gene (PMID 25363760). Additional de novo probably damaging missense variants in KMT2C were identified in ASD probands from the Simons Simplex Collection (Iossifov et al., 2014; Krumm et al., 2015). A de novo LoF variant in KMT2C was identifed in a proband from the Pediatric Cardiac Genetics Consortium who presented with ASD, developmental delay, and intellectual disability in addition to congenital heart disease (Homsy et al., 2015). Koemans et al., 2017 identified four patients with intellectual disability, language delay, and motor delay that carried de novo LoF variants in the KMT2C gene; two of these patients presented with autism, one patient presented with PDD-NOS, and one presented with autistic traits. Three de novo variants (two protein-truncating variants, one missense variant) were identified in ASD probands from the Autism Sequencing Consortium in Satterstrom et al., 2020; subsequent TADA analysis of de novo variants from the Simons Simplex Collection and the Autism Sequencing Consortium and protein-truncating variants from iPSYCH in this report identified KMT2C as a candidate gene with a false discovery rate (FDR) 0.01. Additional de novo loss-of-function variants and potentially damaging missense variants in the KMT2C gene were reported in ASD probands from the SPARK cohort in Zhou et al., 2022; a two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in this report identified KMT2C as a gene reaching exome-wide significance (P < 2.5E-06).
Molecular Function
Histone methyltransferase that methylates 'Lys-4' of histone H3; H3 'Lys-4' methylation represents a specific tag for epigenetic transcriptional activation. Central component of the MLL2/3 complex, a coactivator complex of nuclear receptors, involved in transcriptional coactivation. KMT2C/MLL3 may be a catalytic subunit of this complex.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.
Multilayered genetic dissection of autism: insights from whole-exome sequencing, molecular karyotyping, and cytogenetic analyses in a small Turkish cohort
Unveiling Hidden Genetic Architectures: Molecular Diagnostic Yield of Whole Exome Sequencing in 50 Children With Autism Spectrum Disorder Negative for Copy Number Variations
Mutations in KMT2C have recently been associated with autism spectrum disorder (ASD) in humans. In the conditional knockout model, there is a 50% reduction in the expression levels of KMT2C in both cortical and hippocampal tissue. Though model mice show no change in growth and general locomotor activity, as measured by the accelerating rotarod test and the open field test, they show increases in anxiety, as measured by a decrease in total distance traveled in the center of the open field. Additionally, the model shows changes in social behavior, with increased time spent engaging with a novel mouse in the three-chamber social approach test and increased social dominance in the tube test of social dominance. Model mice also show alterations in spatial learning and memory in the Barnes maze test, with increased latency to find the escape hole and less time spent in the escape hole target region.
Model Type:
Genetic
Model Genotype:
Transgene
Mutation:
Kmt2c knockout mouse models were generated utilizing transgenic mice carrying the CRISPR/Cas9 system (MGI:5583838) to investigate the phenotypic consequences of KMT2C loss of function. Using adeno-associated viruses (AAV) as delivery vectors, exon 3 of KMT2C was targeted with sgRNA in newborn mice to produce the knockout of the gene.
Allele Type: Conditional knockout
Strain of Origin: (129X1/SvJ x 129S1/Sv)F1-Kitl+
Genetic Background: C57BL/6J
ES Cell Line: R1
Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
A Kmt2c loss-of-function model organism, was generated by introducing mutations in a canonical exon of Kmt2c of mice via non-homologous end joining using the CRISPR/Cas9 system. The resulting Kmt2c heterozygous mutant mice (Kmt2c^+/fs mice) carry a 19-bp deletion in exon 43 of the mutant allele, which results in a frameshift mutation. Heterozygous mice were crossed to generate Kmt2c homozygous mutant mice (Kmt2c^fs/fs).
Allele Type: Knockout
Strain of Origin: C57BL/6N
Genetic Background: C57BL/6N
ES Cell Line: Not reported
Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
A Kmt2c haploinsufficiency model organism, was generated by introducing mutations in a canonical exon of Kmt2c of mice via non-homologous end joining using the CRISPR/Cas9 system. The resulting Kmt2c heterozygous mutant mice (Kmt2c^+/fs mice) carry a 19-bp deletion in exon 43 of the mutant allele, which results in a frameshift mutation.
Allele Type: Knockout
Strain of Origin: C57BL/6N
Genetic Background: C57BL/6N
ES Cell Line: Not reported
Mutant ES Cell Line: Model Source:
Description: Kmt2c mutant mice displayed a significant increase in self-grooming episodes compared to controls.
Exp Paradigm: same sex pairs (mutant-control vs. control-control)
Description: Kmt2c mutant mice exhibited no significant difference in the frequency of nose-nose or nose-head interactions. However, mutant mice exhibited a significant decrease in the number of nose-anogenital interactions.
Exp Paradigm: same sex pairs (mutant-control vs. control-control)
Description: Kmt2c mutant mice won a significantly greater number of times against control animals in the test tube, as expressed by percentage of victories per day.
Description: While Kmt2c mutant mice exhibited no change in time spent in the center versus periphery compared to controls, they exhibited significantly decreased distance travelled in the center compared to controls.
Description: When the time spent directly interacting with the novel mouse or novel object was analyzed, it was found that Kmt2c mutant mice spent significantly more time engaging directly with the novel mouse and novel object compared to controls.
Description: After the escape hole was moved to a novel location, Kmt2c mutant mice exhibited a significant decrease in the amount of time spent in the target region compared to controls.
Description: Kmt2c mutant mice exhibited no significant difference in total distance travelled compared to controls. However, mutant mice exhibited a significant increase in the time taken to reach the escape hole for the first time, some never reaching the escape hole.
Cued or contextual fear conditioning: memory of context: long term recall1
Decreased
Description: 24 hours after electric shock fear conditioning, mutant mice exhibited significantly reduced freezing time during the test phase compared to controls.
Exp Paradigm: Habituation (day 1), Conditioning (day 2), Test phase (day 3): each mouse was placed in the fear conditioning box, allowed to freely explore for 5 min, and returned to its cage. The number of freezing episodes and freezing time was registered.
Description: Kmt2c mutant mice exhibited over 50% reduction in the expression levels of KMT2C in both cortical and hippocampal tissue.
Exp Paradigm: cortical tissue, hippocampal tissue
Description: The expression level of Kmt2c was significantly lower in Kmt2c frameshift mutant mice than in wildtype controls. Protein signal is absent in homozygous mutants, indicating that the frameshift mutation is a true knockout mutation.
Exp Paradigm: Nuclear fraction from whole brain tissue
Description: Kmt2c mutant mice do not show a preference for the chamber with a stranger mouse over the chamber with an empty cage, unlike wildtype mice.
Description: Mutant mice stayed near the previous correct hole for a significantly longer time during the first minute after the removal of the goal in the probe test, which suggests that these mice are less flexible to changes in circumstances.
Description: In a serial reversal test, where mice can drink water only at one of the four corners and the correct corner is changed every day, mutant mice exhibited significantly higher rates of incorrect visits to the corner which opened on the previous day, whereas no significance was observed in those on other days.
Exp Paradigm: Serial reversal
Description: Mutant mice show 3 upregulated and 14 downregulated differentially expressed genes (DEGs) at Benjamini-Hochberg-corrected, and 459 upregulated and 422 downregulated DEGs at uncorrected.
Description: The expression level of Kmt2c was significantly lower in Kmt2c frameshift mutant mice than in wildtype controls.
Exp Paradigm: Nuclear fraction from whole brain tissue
