Novel Form of Congenital Myopathy Caused by Biallelic Mutations in Uncoordinated Mutant Number-45 Myosin Chaperone B

Background: Congenital myopathies (CM) form a genetically heterogeneous group of disorders, and only 60% can be genetically solved.

Methods: We recruited an 11-year-old male of consanguineous parents, presenting with proximal weakness, Gower's sign, without cardiomyopathy with a stable disease course. We performed exome sequencing and data analysis was done by our in-house software Varbank2 according to an autosomal recessive inheritance. We investigated the effect of the missense mutation by complementation assay on the zebrafish steif mutant, an unc-45b loss-of-function model.

Results: We have discovered and published a novel genetically defined form of CM due to a novel homozygous missense mutation in UNC45B (NM_173167.2: c.2261G>A, p.Arg754Gln) also co-segregating in the family with three healthy siblings (Dafsari et al 2019). In our patient's muscle biopsy, core-like structures were detected mainly in the center of muscle fibers in NADH histochemistry. Electron microscopy showed numerous focal core-like alterations of myofibrillar architecture with Z-bands streaming.

Discussion: Three isoforms of UNC45B are highly expressed in skeletal muscle, only one also in cardiac muscle. Due to its high evolutionary conservation throughout species, a loss of UNC45 results in different pathological conditions in various species: a knockdown of unc-45 resulted in dilated cardiomyopathy and a reduced muscle contractility in D. melanogaster. Similarly, in unc-45b knockdown zebrafish and also in steif mutants, disrupted myofibrillogenesis-associated cardiac dysfunction and paralysis was observed. Injection of mutant unc-45b mRNA did not rescue the steif mutant in contrast to wt mRNA confirming the pathogenicity of the missense mutation.

Publication History

Article published online:
28 October 2021