Abstract
Variation in KMT5B is considered a neurodevelopmental disorder risk and correlated to anautism diagnosis in patients. Patient symptoms include hallmark autism phenotypes along
with additional symptoms such as seizures and motor deficits. These motor deficits are
characterized as hypotonia and motor delay. Kmt5b already has a known role in skeletal
muscle, maintaining skeletal muscle stem cell quiescence. However, this was found only in an
adult, repeated injury model. That model is unlikely related to motor deficits exhibited. To
replicate, model, and investigate the effects of KMT5B loss in humans, Kmt5b
haploinsufficient mice were tested. Heterozygous Kmt5b mice expressed numerous
neuromuscular deficits in a sex dependent manner. Male Kmt5b+/- mice exhibited a motor
reflex deficit (evidenced by decreased surface righting, grasp strength, and limb suspension
tests) and hypotonia (evidenced by decreased body weight and skeletal muscle weight).
Female Kmt5b+/- also exhibited hypotonia, but only after puberty. Both sexes of Kmt5b+/- mice
had decreased neuromuscular strength, aberrant neuromuscular junction conformation, and
smaller myofibers. Using tissue-specific Kmt5b loss mouse models, Kmt5b loss only in
skeletal muscle or motor nerves failed to reproduce deficits similar to the global loss model.
Thus, the deficits seen are not caused solely by Kmt5b’s function in either tissue. Finally,
male Kmt5b+/- mice are deficient in endocrine (blood) insulin-like growth hormone 1 (IGF-1).
Therefore, we propose that neuromuscular deficits associated with Kmt5b haploinsufficiency
are not caused by Kmt5b’s role within the neuromuscular system, but rather are caused by
Kmt5b’s effect on IGF-1. This effect has yet to be explored further and is the primary
hypothesis for further investigation.