Abstract
Congenital myopathies (CM) form a genetically heterogeneous group of disorders characterized by perinatal muscle weakness. Here, we report an 11-year old male offspring of consanguineous parents of Lebanese origin. He presented with proximal weakness including Gower’s sign, and skeletal muscle biopsy revealed myopathic changes with core-like structures. Whole exome sequencing of this index patient lead to the discovery of a novel genetically defined CM subtype based on bi-allelic mutations in the uncoordinated mutant number-45 myosin chaperone B (UNC45B) NM_173167:c.2261G > A, p.Arg754Gln. The mutation is conserved in evolution and co-segregates within the pedigree with the phenotype, and located in the myosin binding armadillo repeat domain 3 (ARM3), and has a CADD Score of 35. On a multimeric level, UNC45B aggregates to a chain which serves as an assembly line and functions as a “template” defining the geometry, regularity, and periodicity of myosin arranged into muscle thick filaments. Our discovery is in line with the previously described myopathological phenotypes in C. elegans and in vertebrate mutants and knockdown–models. In conclusion, we here report for the first time a patient with an UNC45B mutation causing a novel genetically defined congenital myopathy disease entity.
Highlights
Congenital myopathies (CM) form a genetically heterogeneous group of disorders characterized by perinatal muscle weakness
(See figure on previous page.) Fig. 1 Phenotypic, myopathological, and electron microscopical findings in our patient with an overview of the uncoordinated mutant number-45 myosin chaperone B (UNC45B) variant identified in this study. a Front and side view of our patient, showing hyperlordosis and obesity. b Gower’s sign in our patient. c Increased fiber size caliber spectrum with internalized nuclei predominantly in hypertrophic muscle fibers and atrophic muscle fibers
The healthy father’s blood sample was unavailable for dideoxy sequencing. h UNC45B multiple sequence alignment made with Jalview shows high evolutionary conservation at amino acid residue p.Arg754 (NP_775259.1 Homo sapiens, the mutated sequence from our patient c.2261G > A p.Arg754Gln, XP_001174363.2 P. troglodytes, XP_0011113905.2 m. mulatta, XP_005624856.1 C. lupus, XP_002695676.1 B. taurus, NP_848795.3 m. musculus, NP_001100498.1 R. norvegicus, XP_004946569.1 g. gallus, NP_705959.1 D. rerio, NP_001172057.1 x. tropicalis, NP_524796.1 D. melanogaster, XP_310258.5 A. gambiae, and NP_497205.1 C. elegans). i Variant in the UNC45B gene (NM_173167.3, 20 exons) identified in our patients and concomitant position in the j
Summary
Congenital myopathies (CM) form a genetically heterogeneous group of disorders characterized by perinatal muscle weakness. His Gower’s time is >10s (Fig. 1b), he is unable to run, shows a Trendelenburg sign (Additional file 1: Figure S1h), he is overweight and has a static disease course. Fiber type distribution was altered as type-2 fibers were virtually absent (Fig. 1d, Additional file 1: Figure S1a).
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