P5.53 The C224W FHL1 mutation is causing a protein aggregation disorder of muscle: Two brothers revisited

Feldkirchner, S.; Walter, Maggie C.; Kubny, C.; Mueller, Steffen; Kress, W.; Hanisch, Franz Georg; Schoser, Benedikt G. H.; Scheßl, J.

doi:10.1016/j.nmd.2011.06.1082

Cited by 1 publication

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“…In a recent publication, a personal communication reported that re-examined SPM tissue was positive for reducing bodies; however, supporting data was not shown (Schessl et al, 2009). 'Cytoplasmic bodies' and 'atypical reducing bodies' were originally observed in XMPMA , and recent reports have revealed that reducing bodies and protein aggregation might occur in XMPMA muscle (Feldkirchner et al, 2011;Feldkirchner et al, 2013). Additionally, cytoplasmic bodies have been observed in a skeletal-muscle biopsy taken from a HCM/EDMD patient with the FHL1 C209R mutation that was investigated here (Knoblauch et al, 2010).…”

Section: Discussionmentioning

confidence: 96%

FHL1 mutations that cause clinically distinct human myopathies form protein aggregates and impair myoblast differentiation

Wilding

Mcgrath

Bonne

et al. 2014

Journal of Cell Science

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FHL1 mutations cause several clinically heterogeneous myopathies, including reducing body myopathy (RBM), scapuloperoneal myopathy (SPM) and X-linked myopathy with postural muscle atrophy (XMPMA). The molecular mechanisms underlying the pathogenesis of FHL1 myopathies are unknown. Protein aggregates, designated 'reducing bodies', that contain mutant FHL1 are detected in RBM muscle but not in several other FHL1 myopathies. Here, RBM, SPM and XMPMA FHL1 mutants were expressed in C2C12 cells and showed equivalent protein expression to wild-type FHL1. These mutants formed aggregates that were positive for the reducing body stain Menadione-NBT, analogous to RBM muscle aggregates. However, hypertrophic cardiomyopathy (HCM) and Emery-Dreifuss muscular dystrophy (EDMD) FHL1 mutants generally exhibited reduced expression. Wild-type FHL1 promotes myoblast differentiation; however, RBM, SPM and XMPMA mutations impaired differentiation, consistent with a loss of normal FHL1 function. Furthermore, SPM and XMPMA FHL1 mutants retarded myotube formation relative to vector control, consistent with a dominant-negative or toxic function. Mutant FHL1 myotube formation was partially rescued by expression of a constitutively active FHL1-binding partner, NFATc1. This is the first study to show that FHL1 mutations identified in several clinically distinct myopathies lead to similar protein aggregation and impair myotube formation, suggesting a common pathogenic mechanism despite heterogeneous clinical features.

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