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.

中文翻译：

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Kmt5b 丢失的性别差异效应

赖氨酸甲基转移酶 5B (KMT5B) 最近被强调为神经发育障碍 (NDD)，特别是自闭症谱系障碍 (ASD) 和智力障碍 (ID) 遗传研究中的风险基因；然而，它在大脑中的作用尚不清楚。这项工作的目标是使用小鼠模型在神经发育上表征 KMT5B 单倍体不足的影响。一个Kmt5b基因陷阱小鼠品系获自 Knockout Mouse Project。对野生型 (WT) 和杂合子 (HET) 小鼠进行全面的神经发育测试，以评估反射、运动行为、学习/记忆、社交行为、重复运动和常见的 ASD 合并症（强迫症、抑郁症和焦虑症）。鉴于在 ASD 患者群体中观察到的强烈性别偏见，我们测试了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 天到成年期，HET 小鼠明显小于 WT 同窝小鼠，这与较小的大脑尺寸（即小头畸形）相关。这在男性中比女性更严重。与 WT 同窝仔相比，HET 雄性新生儿也有睁眼延迟和明显较弱的反射。在年轻人中，观察到与焦虑、抑郁、恐惧和消退学习相关的基因型之间存在显着差异。有趣的是，注意到了几个性别二态差异，包括 HET 女性的重复梳理行为增加和 HET 女性对热板反应的潜伏期增加，而 HET 男性的潜伏期减少。