DataSheet1_KMT5B is required for early motor development.PDF

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.

赖氨酸甲基转移酶5B（KMT5B/SUV4-20H1）的功能破坏性变异已在伴有神经发育表型（涵盖运动功能缺陷，即肌张力低下与运动发育迟缓）的人类个体中被鉴定为可能致病性变异。然而，该酶在早期运动发育过程中的具体作用目前仍未完全阐明。本研究借助Kmt5b基因陷阱小鼠模型，对神经肌肉力量、骨骼肌重量（即肌质量）、神经肌肉接头（neuromuscular junction, NMJ）结构以及肌纤维的类型、尺寸与分布情况进行了评估；实验选取出生后第17天与第44天两个发育时间点，分别代表慢收缩肌与快收缩肌类型的幼年与成年组织结构。在青春期启动前，杂合子雄性小鼠的慢收缩肌重量相较于野生型雄性小鼠显著降低，但该差异未在雌性小鼠中观测到；在年轻成年阶段，我们在两种性别的小鼠中均观测到神经肌肉力量下降、骨骼肌重量（包括慢收缩肌与快收缩肌）降低、神经肌肉接头碎片化程度升高（仅见于慢收缩肌）以及肌纤维尺寸变小的现象。综上，我们认为Kmt5b单倍剂量不足会引发骨骼肌发育缺陷，进而导致肌质量与体重降低。