Differential effects by sex with Kmt5b loss

Abstract

Lysine methyl transferase 5B (KMT5B) has been recently highlighted as a risk gene in genetic studies of neurodevelopmental disorders (NDDs), specifically, autism spectrum disorder (ASD) and intellectual disability (ID); yet, its role in the brain is not known. The goal of this work was to neurodevelopmentally characterize the effect(s) of KMT5B haploinsufficiency using a mouse model. A Kmt5b gene‐trap mouse line was obtained from the Knockout Mouse Project. Wild type (WT) and heterozygous (HET) mice were subjected to a comprehensive neurodevelopmental test battery to assess reflexes, motor behavior, learning/memory, social behavior, repetitive movement, and common ASD comorbidities (obsessive compulsion, depression, and anxiety). Given the strong sex bias observed in the ASD patient population, we tested both a male and female cohort of animals and compared differences between genotypes and sexes. HET mice were significantly smaller than WT littermates starting at postnatal day 10 through young adulthood which was correlated with smaller brain size (i.e., microcephaly). This was more severe in males than females. HET male neonates also had delayed eye opening and significantly weaker reflexes than WT littermates. In young adults, significant differences between genotypes relative to anxiety, depression, fear, and extinction learning were observed. Interestingly, 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. Lay Summary Lysine methyl transferase 5B (KMT5B) has been recently highlighted as a risk gene in neurodevelopmental disorders (NDDs), specifically, autism spectrum disorder (ASD) and intellectual disability (ID); yet its role in the brain is not known. Our study indicates that mice lacking one genomic copy of Kmt5b show deficits in neonatal reflexes, sociability, repetitive stress‐induced grooming, changes in thermal pain sensing, decreased depression and anxiety, increased fear, slower extinction learning, and lower body weight, length, and brain size. Furthermore, several outcomes differed by sex, perhaps mirroring the sex bias in ASD.

Refining the Phenotypic Spectrum of KMT5B-Associated Developmental Delay

“…Additionally, while most reported patients were male, the overall small number of patients precludes us from drawing conclusions as to possible sex effects on the phenotype. This is particularly interesting given the aforementioned differential effects by sex suggested by behavioral murine studies ( 8 ). Future studies detailing clinical and molecular characteristics of larger cohorts of patients with KMT5B variants will shed light on these unanswered questions.…”

“…Two additional patients harbor a genomic deletion encompassing KMT5B . Given these variants found in affected individuals, the pLI scores and the aforementioned murine models ( 8 ), the mechanism of disease for this subgroup of patients is haploinsufficiency. In contrast, three previously-reported patients have protein-altering (missense) variants (PAVs).…”

“…Most recently, two mouse models for KMT5B were reported. Using a comprehensive neurodevelopmental test battery, Wickramasekara et al showed differences with regard to anxiety, depression, fear and extinction learning in mice haploinsufficient for KMT5B compared to controls, as well as differential effects by sex ( 8 , 9 ). Wang et al knocked down Kmt5b in the mouse prefrontal cortex and demonstrated social deficits, disruption of glutamatergic synaptic transmission as well as upregulation of genes involved in cellular stress response and ubiquitin-dependent protein degradation ( 10 ).…”

Modelling Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD) Using Mice and Zebrafish

“…Altered brain morphology, decreased sociability, reduced interneurons, increased seizures and anxiety, lack of preference for social novelty and impaired nest-building behaviour [158][159][160][161] Integrin subunit beta 3 (Itgb3) Lack of preference for social novelty, and increased grooming behaviours [162] Lysine methyltransferase 5B (Kmt5b) Deficits in neonatal reflexes and sociability, repetitive grooming, changes in thermal pain sensing, decreased depression and anxiety, increased fear, slower extinction learning, and lower body weight, length, and brain size [163] Methyl-CpG binding protein 2 (Mecp2) Increased social avoidance, abnormal locomotor coordination, deficits in sociability and cognition [116,[164][165][166][167] MET proto-oncogene, receptor tyrosine kinase (Met) Deficits in cognitive function, hippocampal dysfunction [168] MicroRNA 137 (Mir137) Dysregulated synaptic plasticity, repetitive behaviour, and impaired learning and social behaviour [169] Neuronal growth regulator 1 (Negr1)…”

KMT2E haploinsufficiency manifests autistic-like phenotypes and amygdala abnormality in mice

“…We speculate that KMT2Ehaploinsu ciencyhas little effect in acoustic startle and olfactory tests asCHD8 is a key upstream signaling molecule of KMT2E [9]. Compared to another well-known ASDhigh-risk gene Shank3, Shank3 ΔC/ΔC mice(homozygous LOF)are survived;Shank3 +/ΔC mice display only mild social-preference abnormality and no anxiety [14,43].Compared to KMT5B, amember of KMTfamilies, KMT5B -/mice are also highly embryonic lethal but only female KMT5B +/mice display mild abnormality in social-preference and no anxiety [44].These evidencessuggest that ASD/KMT2E LOF and ASD/CHD8 LOF may represent similar ASD subtypes.…”