Neuromuscular Deficits Associated With KMT5B Haploinsufficiency in Mice
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Authors
Hulen, Jason
Issue Date
2022
Volume
Issue
Type
Thesis
Language
en_US
Keywords
Developmental Delay , H4k20 , Histone Methylation , KMT5B , SUV420H1
Alternative Title
Abstract
Variation in KMT5B is considered a neurodevelopmental disorder risk and correlated to an autism 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.
Description
2022
Citation
Publisher
Creighton University
License
Copyright is retained by the Author.
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