The myosin-directed chaperone UNC-45B is essential for sarcomeric organization and muscle function from Caenorhabditis elegans to humans. The pathological impact of UNC-45B in muscle disease remained elusive. We report ten individuals with bi-allelic variants in UNC45B who exhibit childhood-onset progressive muscle weakness. The physiological relevance of these observations was investigated in C. elegans by transgenic expression of conserved UNC-45 missense variants. As one founding member of the UCS family,UNC-45 was first identified in C. elegans, revealing that conditional loss-of -function mutations result in abnormal myofilament assembly and uncoordinated locomotion defects.
Population motility of 60 young adult unc-45(m94) worms expressing the indicated UNC-45 variants on a 24-well plate filled with NGM and seeded with OP50 was measured with the ARENA WMicrotracker system at 25ºC for 24 h after reaching adulthood. Motility data was binned in 15 min time buckets before plotting for easier interpretability.
Myopathy-Related UNC-45B Mutant Missense Proteins Cannot Rescue a Conditional Loss-of-Function Allele. Assessing population motility of 60 worms via an ARENA WMicrotracker reproduced the motility defect on a solid agar surface (Figure 6C). These data suggest that the c.2332C>T (p.Arg778Trp), the c.1207T>C (p.Ser403Pro), and the c.1540T>C (p.Cys514Arg) variants very likely affect UNC-45B protein function. In contrast, expression of the ortholog protein of the p.Arg754Gln variant, UNC-45 (p.Arg767Gln), in the unc-45(m94) background was able to rescue the defect in movement (Figures 6C).
Am J Hum Genet. 2020 Dec 3;107(6):1078-1095. doi: 10.1016/j.ajhg.2020.11.002. Epub 2020 Nov 19.
Donkervoort S, Kutzner CE, Hu Y, Lornage X, Rendu J, Stojkovic T, Baets J, Neuhaus SB, Tanboon J, Maroofian R, Bolduc V, Mroczek M, Conijn S, Kuntz NL, Töpf A, Monges S, Lubieniecki F, McCarty RM, Chao KR, Governali S, Böhm J, Boonyapisit K, Malfatti E, Sangruchi T, Horkayne-Szakaly I, Hedberg-Oldfors C, Efthymiou S, Noguchi S, Djeddi S, Iida A, di Rosa G, Fiorillo C, Salpietro V, Darin N, Fauré J, Houlden H, Oldfors A, Nishino I, de Ridder W, Straub V, Pokrzywa W, Laporte J, Foley AR, Romero NB, Ottenheijm C, Hoppe T, Bönnemann CG.