Department of Pharmacology & Neuroscience, School of Medicine, Creighton University, Omaha, Nebraska, USA.
Autism Res. 2021 Aug;14(8):1554-1571. doi: 10.1002/aur.2516. Epub 2021 Apr 19.
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.
赖氨酸甲基转移酶 5B（KMT5B）最近在神经发育障碍（NDD）的遗传研究中被强调为一个风险基因，特别是在自闭症谱系障碍（ASD）和智力障碍（ID）中；然而，其在大脑中的作用尚不清楚。本研究的目的是使用小鼠模型对 KMT5B 杂合不足的神经发育影响进行特征描述。从 Knockout Mouse Project 获得了 Kmt5b 基因捕获小鼠品系。野生型（WT）和杂合型（HET）小鼠接受了全面的神经发育测试，以评估反射、运动行为、学习/记忆、社会行为、重复性运动以及常见的 ASD 合并症（强迫症、抑郁和焦虑）。鉴于在 ASD 患者群体中观察到强烈的性别偏见，我们测试了一个雄性和雌性动物队列，并比较了基因型和性别之间的差异。从出生后第 10 天到成年早期，HET 小鼠明显小于 WT 同窝仔鼠，这与大脑体积较小（即小头症）有关。雄性比雌性更严重。HET 雄性新生鼠的睁眼反射也明显弱于 WT 同窝仔鼠。在成年早期，与焦虑、抑郁、恐惧和消退学习相关的基因型差异显著。有趣的是，注意到了一些性别二态性差异，包括 HET 雌性的重复性梳理行为增加，HET 雌性的热板反应潜伏期增加，而 HET 雄性的潜伏期减少。
