Investigating how Mylpf-regulated sarcomere formation influences limb skeletal development

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Investigating how Mylpf-regulated sarcomere formation influences limb skeletal development In arthrogryposis, babies are born with at least two limbs with hand or foot showing contractures; it most commonly manifests as clubfoot, and it is found in roughly 1 in 4000 live births. Arthrogryposis causes impaired movement and can require many surgeries through a lifetime to correct. The disease is characterized by skeletal joint defects, but it is caused by impaired muscle movement in utero. We recently found that the muscle-expressed gene Mylpf is vital not only to normal actin movement, but also for muscle fiber integrity and that variants in human MYLPF cause Distal Arthrogryposis Type 1 (DA1). Mylpf protein binds to the myosin heavy chain near head region which moves actin during muscle contraction. We discovered that zebrafish mylpfa mutant larvae display a phenotype consistent with DA1, including impaired myosin activity, reduced muscle force overall, and complete fin paralysis. Surprisingly, we find that Mylpf function is needed not only for normal contraction, but also for the assembly of actin and myosin into the fundamental unit of muscle, called sarcomeres. In unpublished work we find that sarcomeres form poorly in mylpfa mutants, lacking one of two Mylpf genes, and are completely absent in mylpfa;mylpfb double mutants, which lack all Mylpf function. We hypothesize that Mylpf function prevents distal arthrogryposis by promoting association of sarcomeric components during the critical window of embryonic development when limb joints are forming. To test this hypothesis, we will (Aim 1) investigate the role of Mylpf in sarcomere assembly, (Aim 2a) investigate how the human MYLPF gene variants cause this musculo-skeletal disease, and (Aim 2b) when the skeletal defects can be corrected.