TY  - JOUR
A1  - Kölbel, Heike
A1  - Roos, Andreas
A1  - van der Ven, Peter F. M.
A1  - Evangelista, Teresinha
A1  - Nolte, Kay
A1  - Johnson, Katherine
A1  - Töpf, Ana
A1  - Wilson, Michael
A1  - Kress, Wolfram
A1  - Sickmann, Albert
A1  - Straub, Volker
A1  - Kollipara, Laxmikanth
A1  - Weis, Joachim
A1  - Fürst, Dieter O.
A1  - Schara, Ulrike
T1  - First clinical and myopathological description of a myofibrillar myopathy with congenital onset and homozygous mutation in FLNC
JF  - Human Mutation
N2  - 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.
KW  - congenital myopathy
KW  - filamin C
KW  - myofibrillar myopathy
KW  - proteomic signature
KW  - recessive inheritance
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-215481
VL  - 41
IS  - 9
SP  - 1600
EP  - 1614
ER  - 
TY  - JOUR
A1  - Böhm, Johann
A1  - Vasli, Nasim
A1  - Maurer, Marie
A1  - Cowling, Belinda
A1  - Shelton, G. Diane
A1  - Kress, Wolfram
A1  - Toussaint, Anne
A1  - Prokic, Ivana
A1  - Schara, Ulrike
A1  - Anderson, Thomas James
A1  - Weis, Joachim
A1  - Tiret, Laurent
A1  - Laporte, Jocelyn
T1  - Altered Splicing of the BIN1 Muscle-Specific Exon in Humans and Dogs with Highly Progressive Centronuclear Myopathy
JF  - PLOS Genetics
N2  - Amphiphysin 2, encoded by BIN1, is a key factor for membrane sensing and remodelling in different cell types. Homozygous BIN1 mutations in ubiquitously expressed exons are associated with autosomal recessive centronuclear myopathy (CNM), a mildly progressive muscle disorder typically showing abnormal nuclear centralization on biopsies. In addition, misregulation of BIN1 splicing partially accounts for the muscle defects in myotonic dystrophy (DM). However, the muscle-specific function of amphiphysin 2 and its pathogenicity in both muscle disorders are not well understood. In this study we identified and characterized the first mutation affecting the splicing of the muscle-specific BIN1 exon 11 in a consanguineous family with rapidly progressive and ultimately fatal centronuclear myopathy. In parallel, we discovered a mutation in the same BIN1 exon 11 acceptor splice site as the genetic cause of the canine Inherited Myopathy of Great Danes (IMGD). Analysis of RNA from patient muscle demonstrated complete skipping of exon 11 and BIN1 constructs without exon 11 were unable to promote membrane tubulation in differentiated myotubes. Comparative immunofluorescence and ultrastructural analyses of patient and canine biopsies revealed common structural defects, emphasizing the importance of amphiphysin 2 in membrane remodelling and maintenance of the skeletal muscle triad. Our data demonstrate that the alteration of the muscle-specific function of amphiphysin 2 is a common pathomechanism for centronuclear myopathy, myotonic dystrophy, and IMGD. The IMGD dog is the first faithful model for human BIN1-related CNM and represents a mammalian model available for preclinical trials of potential therapies.
KW  - linked myotubular myopathy
KW  - skeletal muscle
KW  - inherited myopathy
KW  - SH3 domain
KW  - amphiphysin-2 BIN1
KW  - membrane curvature
KW  - tumor-suppressor
KW  - great dane
KW  - mutation
KW  - gene
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-127590
SN  - 1553-7404
VL  - 9
IS  - 6
ER  -