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Acta Neuropathol Commun. 2019 Dec 18;7(1):211. doi: 10.1186/s40478-019-0869-1.

Bi-allelic mutations in uncoordinated mutant number-45 myosin chaperone B are a cause for congenital myopathy.

Author information

1
Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937, Cologne, Germany.
2
Center for Molecular Medicine (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937, Cologne, Germany.
3
Institute of Neuropathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.
4
Center for Rare Diseases, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937, Cologne, Germany.
5
Institute of Neuropathology, RWTH University Hospital, 52074, Aachen, Germany.
6
Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937, Cologne, Germany. sebahattin.cirak@uk-koeln.de.
7
Center for Molecular Medicine (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937, Cologne, Germany. sebahattin.cirak@uk-koeln.de.
8
Center for Rare Diseases, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937, Cologne, Germany. sebahattin.cirak@uk-koeln.de.

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.

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