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Pathogenic variants in KMT5B , a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM # 617788). Given the relatively recent discovery of this disorder, it has not been fully characterized. Deep phenotyping of the largest ( n  = 43) patient cohort to date identified that hypotonia and congenital heart defects are prominent features that were previously not associated with this syndrome. Both missense variants and putative loss-of-function variants resulted in slow growth in patient-derived cell lines. KMT5B homozygous knockout mice were smaller in size than their wild-type littermates but did not have significantly smaller brains, suggesting relative macrocephaly, also noted as a prominent clinical feature. RNA sequencing of patient lymphoblasts and Kmt5b haploinsufficient mouse brains identified differentially expressed pathways associated with nervous system development and function including axon guidance signaling. Overall, we identified additional pathogenic variants and clinical features in KMT5B -related neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems.

Disruptive variants in lysine methyl transferase 5B (KMT5B/SUV4-20H1) have been identified as likely-pathogenic among humans with neurodevelopmental phenotypes including motor deficits (i.e., hypotonia and motor delay). However, the role that this enzyme plays in early motor development is largely unknown. Using a Kmt5b gene trap mouse model, we assessed neuromuscular strength, skeletal muscle weight (i.e., muscle mass), neuromuscular junction (NMJ) structure, and myofiber type, size, and distribution. Tests were performed over developmental time (postnatal days 17 and 44) to represent postnatal versus adult structures in slow- and fast-twitch muscle types. Prior to the onset of puberty, slow-twitch muscle weight was significantly reduced in heterozygous compared to wild-type males but not females. At the young adult stage, we identified decreased neuromuscular strength, decreased skeletal muscle weights (both slow- and fast-twitch), increased NMJ fragmentation (in slow-twitch muscle), and smaller myofibers in both sexes. We conclude that Kmt5b haploinsufficiency results in a skeletal muscle developmental deficit causing reduced muscle mass and body weight., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hulen, Kenny, Black, Hallgren, Hammond, Bredahl, Wickramasekara, Abel and Stessman.)

Neurogenesis is an elegantly coordinated developmental process that must maintain a careful balance of proliferation and differentiation programs to be compatible with life. Due to the fine-tuning required for these processes, epigenetic mechanisms (e.g., DNA methylation and histone modifications) are employed, in addition to changes in mRNA transcription, to regulate gene expression. The purpose of this review is to highlight what we currently know about histone 4 lysine 20 (H4K20) methylation and its role in the developing brain. Utilizing publicly-available RNA-Sequencing data and published literature, we highlight the versatility of H4K20 methyl modifications in mediating diverse cellular events from gene silencing/chromatin compaction to DNA double-stranded break repair. From large-scale human DNA sequencing studies, we further propose that the lysine methyltransferase gene, KMT5B (OMIM: 610881), may fit into a category of epigenetic modifier genes that are critical for typical neurodevelopment, such as EHMT1 and ARID1B , which are associated with Kleefstra syndrome (OMIM: 610253) and Coffin-Siris syndrome (OMIM: 135900), respectively. Based on our current knowledge of the H4K20 methyl modification, we discuss emerging themes and interesting questions on how this histone modification, and particularly KMT5B expression, might impact neurodevelopment along with current challenges and potential avenues for future research.

Cluster of differentiation 44 (Cd44), a hyaluronan receptor, and the secreted hyaluronan-binding protein Inter-α-trypsin Inhibitor Heavy chain 3 (Itih3) play an important role in cancer and oxidative stress. Smoking of tobacco reduces Itih3 in the plasma and activates hyaluronan signaling through Cd44, but the impact of Cd44 on Itih3 expression is unknown. Here, we studied changes induced by the tobacco component nicotine on the glutathione (GSH) antioxidant system and Itih3 gene expression in Cd44 knockout mice. Cd44 deficiency decreased baseline total GSH and oxidized glutathione (GSSG) levels in the liver compared to wildtype mice. However, contrary to wildtype mice, chronic oral nicotine administration (200 μg/ml) failed to further reduce total GSH and GSSG in Cd44 mice. Sex differences with lowered glutathione levels in females was also detectable only in wildtype but not Cd44 knockout mice. Itih3 mRNA levels in the liver and hypothalamus were not affected by nicotine, Cd44 genotype or sex. Nonetheless, the correlation between Itih3 and total GSH levels in the liver (r = 0.42, p < 0.05) suggested a role of Itih3 in glutathione metabolism in WT mice. Again this effect was diminished in Cd44 knockout mice. The disappearance of nicotine effects, sex differences and correlations between Itih3 and total GSH in Cd44 knockout mice compared to wildtype animals suggests an interaction between nicotine, Cd44 and/or sex-dependent signaling in the regulation of glutathione metabolism.