O.18Recessive mutations in the myosin chaperone UNC-45B impair muscle myofibrillar integrity, manifesting as progressive myopathy with eccentric cores

UNC-45B (unc45 myosin chaperone B) encodes a myosin-specific co-chaperone essential for the folding, stability and maintenance of sarcomeric myosins, thus facilitating proper assembly and function of myosins in skeletal and cardiac muscle. However, mutations in UNC-45B have not yet been established as a cause for muscle disease. We report 3 independent patients with a phenotype of childhood-onset progressive proximal and axial muscle weakness and respiratory insufficiency whose muscle biopsy findings include "eccentric" and unstructured cores with accumulation of Z-disc material. Whole exome sequencing identified rare, predicted to be damaging, bi-allic mutations in the C-terminal UCS domain of UNC-45B which is critical for myosin binding. The recurring c. 2261G>A; p.Arg754Gln UNC-45B mutation was identified in homozygosity in two patients of Hispanic and Turkish descent respectively, while the third patient was found to have a rare bi-allic missense mutation c.2332C>T; p.Arg778Trp in compound heterozygosity with a splice site mutation c.2261+5G>C resulting in aberrant splicing. Western blot revealed a severe reduction of UNC-45B protein in patient muscle compared to control, and immunofluorescence localization studies demonstrated abnormal relocalization of the residual UNC-45B protein within the sarcomere as well as focal disruption of the myofibrillar apparatus. Functional analyses of the effect of these UNC-45B mutations on muscle fiber mechanics, through force generation and myosin binding in patient's muscle, in addition to in vivo studies in C.elegans of the effect of these mutations on UNC45b function will provide further insights into this novel disease mechanism. Our series establishes recessive mutations in UNC-45B as a cause of a novel form of progressive myopathy in humans, which we propose to be classified as a secondary myosinopathy, manifesting histologically and ultrastructurally with eccentric and unstructured cores.