Neuropediatrics 2021; 52(S 01): S1-S53
DOI: 10.1055/s-0041-1739597
Poster Abstracts

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

Autoren

  • Sebahattin Cirak

    1   Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Germany
    2   Center for Molecular Medicine (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, Germany
    3   Center for Rare Diseases, Faculty of Medicine and University Hospital Cologne, University of Cologne, Germany

  • Hülya-Sevcan Daimagüler

    1   Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Germany
    2   Center for Molecular Medicine (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, Germany

  • Federica Diofano

    4   Molecular Cardiology, Department of Internal Medicine II, Ulm University, Ulm, Germany

  • Hormos Salimi Dafsari

    1   Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Germany
    2   Center for Molecular Medicine (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, Germany

  • Anna Brunn

    5   Institute of Neuropathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Germany

  • Joachim Weis

    6   Institute of Neuropathology, RWTH University Hospital, Aachen, Germany

  • Martina Deckert

    3   Center for Rare Diseases, Faculty of Medicine and University Hospital Cologne, University of Cologne, Germany

  • Peter Nürnberg

    7   Cologne Center for Genetics (CCG), University Hospital Cologne, Cologne, Germany

  • Steffen Just

    4   Molecular Cardiology, Department of Internal Medicine II, Ulm University, Ulm, Germany
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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.



Publikationsverlauf

Artikel online veröffentlicht:
28. Oktober 2021

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