A de novo missense variant in the KAT6B gene was identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014), while a paternally-inherited nonsense variant in this gene was identified in an ASD proband from the SPARK cohort (Feliciano et al., 2019). Additional de novo variants in KAT6B have been identified in probands with intellectual disability (Lelieveld et al., 2016) and from the Deciphering Developmental Disorders 2017 study. Single-molecular molecular inversion probe (smMIP) sequencing of 7,954 probands from cohorts with a primary diagnosis of ASD in Wang et al., 2020 identified one individual with a likely-gene disruptive variant and 17 individuals with missense variants with CADD scores 30 in the KAT6B gene.
Molecular Function
The protein encoded by this gene is a histone acetyltransferase and component of the MOZ/MORF protein complex. In addition to its acetyltransferase activity, the encoded protein has transcriptional activation activity in its N-terminal end and transcriptional repression activity in its C-terminal end. This protein is necessary for RUNX2-dependent transcriptional activation and could be involved in brain development. Heterozygous mutations in KAT6B have been found in patients with genitopatellar syndrome (OMIM 606170) and SBBYSS syndrome (OMIM 603736).
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders
Next-generation phenotyping integrated in a national framework for patients with ultrarare disorders improves genetic diagnostics and yields new molecular findings
Phenotypic and genetic analysis of children with unexplained neurodevelopmental delay and neurodevelopmental comorbidities in a Chinese cohort using trio-based whole-exome sequencing
KAT6B haploinsufficient mice are a model for Say-Barber-Biesecker- Young-Simpson syndrome. The normal function of KAT6B is as a lysine acetyltransferase. In the mouse model there is a deficiency of histone H3 lysine 9 acetylation. The haploinsufficient model has behavioral deficits in spatial learning and memory, in sociability and social memory, decreased anxiety behavior and decreased startle response. VPA, a lysine acetyltransferase inhibitor and ALCAR, an acetyl donor are tested in the restoration of phenotypes. VPA restores anxiety, sociability but does not restore cognitive impairments. ALCAR restores anxiety, sociability and cognitive phenotypes.
References
Type
Title
Author, Year
Primary
Increasing histone acetylation improves sociability and restores learning and memory in KAT6B-haploinsufficient mice
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
The Kat6b locus was targeted to flank Kat6b exons 2 to 12 with loxP sites. Kat6b floxed mice were crossed to a Cre-deleter strain, resulting in the Cre-recombinaseâ??mediated deletion of exons 2â??12 of the Kat6b gene, creating a Kat6b-null allele (Kat6b^-). The deleted sequence encoded the N-terminal conserved (NEMM) domain, double plant homeodomain fingers (PHD), and the catalytic MYST histone acetyltransferase domain as well as alternative splice sites. Mice were back-crossed to C57BL/6 mice for more than 10 generations. Heterozygous mice were crossed to generate homozygous knockouts (Kat6b^-/-).
Allele Type: Knockout
Strain of Origin: Not reported
Genetic Background: C57BL/6
ES Cell Line: C57BL/6 x 129Sv
Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
The Kat6b locus was targeted to flank Kat6b exons 2 to 12 with loxP sites. Kat6b floxed mice were crossed to a Cre-deleter strain, resulting in the Cre-recombinaseâ??mediated deletion of exons 2â??12 of the Kat6b gene, creating a Kat6b-null allele (Kat6b^-). The deleted sequence encoded the N-terminal conserved (NEMM) domain, double plant homeodomain fingers (PHD), and the catalytic MYST histone acetyltransferase domain as well as alternative splice sites. Mice were back-crossed to C57BL/6 mice for more than 10 generations. Heterozygous mice carry one copy of the null allele (Kat6b^+/-).
Allele Type: Knockout
Strain of Origin: Not reported
Genetic Background: C57BL/6
ES Cell Line: C57BL/6 x 129Sv
Mutant ES Cell Line: Model Source:
Description: A lower percentage of heterozygous animals vocalize, and there is a reduced number of overall USVs in the animals that do vocalize. The proportions of specific subtypes of vocalizations were largely similar between genotypes.
Description: Heterozygous mice show an increase of 50% in the percent of time in open section, and a 74% increase in the number of entries to the open section, and increased distance traveled in the open section of the elevated zero maze.
Description: Heterozygous mice show an 18% decrease in acetylation at H3K9, but no change in H3K23 or H3K14 in the cortex at E18.5. H3K9 acetylation is also decreased in the cortex at but not at 3 weeks. H3K9 acetylation is decreased in adult white blood cells while H3K23 acetylation is not changed.
