%0 Journal Article
%T Pathogenic Variants in the Myosin Chaperone UNC-45B Cause Progressive Myopathy with Eccentric Cores.
%A Donkervoort S
%A Kutzner CE
%A Hu Y
%A Lornage X
%A Rendu J
%A Stojkovic T
%A Baets J
%A Neuhaus SB
%A Tanboon J
%A Maroofian R
%A Bolduc V
%A Mroczek M
%A Conijn S
%A Kuntz NL
%A Töpf A
%A Monges S
%A Lubieniecki F
%A McCarty RM
%A Chao KR
%A Governali S
%A Böhm J
%A Boonyapisit K
%A Malfatti E
%A Sangruchi T
%A Horkayne-Szakaly I
%A Hedberg-Oldfors C
%A Efthymiou S
%A Noguchi S
%A Djeddi S
%A Iida A
%A di Rosa G
%A Fiorillo C
%A Salpietro V
%A Darin N
%A Fauré J
%A Houlden H
%A Oldfors A
%A Nishino I
%A de Ridder W
%A Straub V
%A Pokrzywa W
%A Laporte J
%A Foley AR
%A Romero NB
%A Ottenheijm C
%A Hoppe T
%A Bönnemann CG
%J Am J Hum Genet
%V 107
%N 6
%D 12 2020 3
%M 33217308
%F 11.043
%R 10.1016/j.ajhg.2020.11.002
%X 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. We identified a common UNC45B variant that acts as a complex hypomorph splice variant. Purified UNC-45B mutants showed changes in folding and solubility. In situ localization studies further demonstrated reduced expression of mutant UNC-45B in muscle combined with abnormal localization away from the A-band towards the Z-disk of the sarcomere. The physiological relevance of these observations was investigated in C. elegans by transgenic expression of conserved UNC-45 missense variants, which showed impaired myosin binding for one and defective muscle function for three. Together, our results demonstrate that UNC-45B impairment manifests as a chaperonopathy with progressive muscle pathology, which discovers the previously unknown conserved role of UNC-45B in myofibrillar organization.