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First clinical and myopathological description of a myofibrillar myopathy with congenital onset and homozygous mutation in FLNC

Lookup NU author(s): Dr Katherine JohnsonORCiD, Dr Ana TopfORCiD, Professor Volker StraubORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2020 The Authors. Human Mutation published by Wiley Periodicals LLC. Filamin C (encoded by the FLNC gene) is a large actin-cross-linking protein involved in shaping the actin cytoskeleton in response to signaling events both at the sarcolemma and at myofibrillar Z-discs of cross-striated muscle cells. Multiple mutations in FLNC are associated with myofibrillar myopathies of autosomal-dominant inheritance. Here, we describe for the first time a boy with congenital onset of generalized muscular hypotonia and muscular weakness, delayed motor development but no cardiac involvement associated with a homozygous FLNC mutation c.1325C>G (p.Pro442Arg). We performed ultramorphological, proteomic, and functional investigations as well as immunological studies of known marker proteins for dominant filaminopathies. We show that the mutant protein is expressed in similar quantities as the wild-type variant in control skeletal muscle fibers. The proteomic signature of quadriceps muscle is altered and ultrastructural perturbations are evident. Moreover, filaminopathy marker proteins are comparable both in our homozygous and a dominant control case (c.5161delG). Biochemical investigations demonstrate that the recombinant mutant protein is less stable and more prone to degradation by proteolytic enzymes than the wild-type variant. The unusual congenital presentation of the disease clearly demonstrates that homozygosity for mutations in FLNC severely aggravates the phenotype.

Publication metadata

Author(s): Kolbel H, Roos A, van der Ven PFM, Evangelista T, Nolte K, Johnson K, Topf A, Wilson M, Kress W, Sickmann A, Straub V, Kollipara L, Weis J, Furst DO, Schara U

Publication type: Article

Publication status: Published

Journal: Human Mutation

Year: 2020

Volume: 41

Issue: 9

Pages: 1600-1614

Print publication date: 01/09/2020

Online publication date: 09/06/2020

Acceptance date: 07/06/2020

Date deposited: 12/07/2021

ISSN (print): 1059-7794

ISSN (electronic): 1098-1004

Publisher: John Wiley and Sons Inc.


DOI: 10.1002/humu.24062

PubMed id: 32516863


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