A de novo loss-of-function (LoF) variant in the KMT5B gene (previously known as SUV420H1) was identified in an autistic proband from a simplex family in Iossifov et al., 2012 (PMID 22542183). In addition, two missense variants in the KMT5B gene that were predicted to be deleterious was also identified in ASD probands from the Simons Simplex Collection in Sanders et al., 2012 (PMID 22495306). Although population rate is not provided, many missense variants are listed in the NHLBI Exome Sequencing Project's Exome Variant Viewer for this gene. Two additional de novo LoF variants in this gene were identified in ASD probands from the Autism Sequencing Consortium in De Rubeis et al., 2014 (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) in this report identified KMT5B as a gene meeting high statistical significance with a FDR 0.01, meaning that this gene had a 99% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). 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 Zhou et al., 2022 identified KMT5B as a gene reaching exome-wide significance (P < 2.5E-06). Additional de novo variants in KMT5B have been identified in individuals with ASD and/or developmental delay/intellectual disability (Stessman et al., 2017; Yuen et al., 2017).
Molecular Function
Histone methyltransferase that specifically trimethylates 'Lys-20' of histone H4. H4 'Lys-20' trimethylation represents a specific tag for epigenetic transcriptional repression. Mainly functions in pericentric heterochromatin regions, thereby playing a central role in the establishment of constitutive heterochromatin in these regions. KMT5B is targeted to histone H3 via its interaction with RB1 family proteins (RB1, RBL1 and RBL2). Plays a role in myogenesis by regulating the expression of target genes, such as EID3.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
De novo mutations revealed by whole-exome sequencing are strongly associated with autism.
Autism risk gene KMT5B deficiency in prefrontal cortex induces synaptic dysfunction and social deficits via alterations of DNA repair and gene transcription
KMT5B het KO mice show decrease in size starting at postnatal day 10 through young adulthood, decrease in brain size (i.e., microcephaly) which was more severe in males than females. delayed eye opening and significantly weaker reflexes in males, abnormal anxiety, depression, fear, extinction learning, increased grooming. Several sexually dimorphic differences were noted including increased repetitive grooming behavior in het females and an increased latency to hot plate response in HET females versus a decreased latency in HET males (Wickramasekara RN, Aut Res, 2021).
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
The gene trapping strategy makes Kmt5b^tm1a(KOMP)Wtsi mice effectively heterozygous for Kmt5b. Insertion of the gene trap cassette between Kmt5b exons 4 and 5 results in splicing from exon 4 to the en2 sa (splice acceptor) site in the cassette which drives the expression of the LacZ/Neo selectable marker immediately terminated by a polyadenylation signal. The construct creates an early truncation upstream of the Kmt5b functional set domain.
Allele Type: Knockout
Strain of Origin: C57BL/6N
Genetic Background: C57BL/6N
ES Cell Line: JM8.N4
Mutant ES Cell Line: NA
Model Source: Wellcome Trust Sanger Institute
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
The gene trapping strategy makes Kmt5b^tm1a(KOMP)Wtsi mice effectively heterozygous for Kmt5b. Insertion of the gene trap cassette between Kmt5b exons 4 and 5 results in splicing from exon 4 to the en2 sa (splice acceptor) site in the cassette which drives the expression of the LacZ/Neo selectable marker immediately terminated by a polyadenylation signal. The construct creates an early truncation upstream of the Kmt5b functional set domain.
Allele Type: Knockout
Strain of Origin: C57BL/6N
Genetic Background: C57BL/6N
ES Cell Line: JM8.N4
Mutant ES Cell Line: NA
Model Source: Wellcome Trust Sanger Institute
Description: Linear regression analysis between body weight and time to right showed a significant correlation among het females; male het but not female het mice are significantly slower to right from a supine position; sexual dimorphism
Description: Neuromuscular junction (NMJ) occupancy (defined as the ratio of nerve/vesicular area vs. muscular NMJ area) did not significantly differ in the soleus (SOL) or the extensor digitorum longus (EDL) of Kmt5b heterozygotes compared to wildtype mice. No significant differences were identified in nerve/vesicular NMJ area or continuity in either muscle. In the muscle portion of the NMJ, SOL NMJ areas did not differ, but heterozygote NMJs had increased discontinuity compared to wildtype NMJs. A trend toward increased discontinuity among heterozygotes was noted in the EDL but was not statistically significant.
Description: Increased number head grooming initiations in het females compared to wt females after stress stimulus ; no change in novelty-induced or stress-induced grooming; repeated head-body grooming pattern increased in het compared to wt females; sexual dimorphism
Description: There was a significant decrease in soleus muscle (SOL) weight in Kmt5b heterozygous male mice but no differences in extensor digitorum longus muscle (EDL) weight compared to wildtype mice at P17. In addition, both SOL and EDL muscles in Kmt5b heterozygous mice weighed less than in wildtype mice at P44. After normalization to body weight, SOL muscle weight of Kmt5b heterozygous male mice at P17 were much lower compared to wildtype male mice, but no differences were seen in normalized EDL weights of mice. There were no significant differences in normalized P44 SOL weights of Kmt5b heterozygous mice. However, female heterozygous normalized P44 EDL weights remained modestly lower after post hoc testing.
Description: There were no significant differences in neuromuscular strength in Kmt5b heterozygous mice at P17. However, Kmt5b heterozygous mice displayed less neuromuscular strength compared to wildtype mice at P44.
Description: In the slow-twitch soleus (SOL) muscle, there were no differences in myofiber number at P17. There were no significant differences among relative proportions either by count or area of myofiber compositions of either male or female SOL or extensor digitorum longus (EDL) muscles of Kmt5b heterozygous and wildtype mice at P17. However, P44 Kmt5b heterozygous females had increased SOL type IIa myofiber number compared to wildtype females. In the fast-twitch EDL muscle, Kmt5b heterozygous mice had significantly greater type IIb myofiber number at P44 compared to wildtype mice. Kmt5b heterozygous females had increased EDL type IIb myofibers at P44 compared to wildtype females. There were no significant differences among relative proportions either by count or ar
Description: No differences in incisor eruption, pinna folding, or vaginal opening in females, delayed eye opening primarily in males, sexual dimorphism
