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Novel Filamin C Myofibrillar Myopathy Variants Cause Different Pathomechanisms and Alterations in Protein Quality
Dominik Sellung1, Lorena Heil2, Nassam Daya1
1Department of Neurology, Heimer Institute for Muscle Research, University Hospital Bergmannsheil, Ruhr-University Bochum, 44789 Bochum, Germany.
Abstract:
Myofibrillar myopathies (MFM) are a group of chronic muscle diseases pathophysiologically characterized by accumulation of protein aggregates and structural failure of muscle fibers. A subtype of MFM is caused by heterozygous mutations in the filamin C (FLNC) gene, exhibiting progressive muscle weakness, muscle structural alterations and intracellular protein accumulations. Here, we characterize in depth the pathogenicity of two novel truncating FLNc variants (p.Q1662X and p.Y2704X) and assess their distinct effect on FLNc stability and distribution as well as their impact on protein quality system (PQS) pathways. Both variants cause a slowly progressive myopathy with disease onset in adulthood, chronic myopathic alterations in muscle biopsy including the presence of intracellular protein aggregates. Our analyses revealed that p.Q1662X results in FLNc haploinsufficiency and p.Y2704X in a dominant-negative FLNc accumulation. Moreover, both protein-truncating variants cause different PQS alterations: p.Q1662X leads to an increase in expression of several genes involved in the ubiquitin-proteasome system (UPS) and the chaperone-assisted selective autophagy (CASA) system, whereas p.Y2704X results in increased abundance of proteins involved in UPS activation and autophagic buildup. We conclude that truncating FLNC variants might have different pathogenetic consequences and impair PQS function by diverse mechanisms and to varying extents. Further studies on a larger number of patients are necessary to confirm our observations.
Insights
Two novel filamin C (FLNC) gene variants cause adult-onset myopathy by disrupting muscle fiber structure and protein quality systems differently. Further research is needed to confirm these findings in larger patient cohorts.
Area of Science:
- Genetics and Molecular Biology
- Neurology
- Cell Biology
Background:
- Myofibrillar myopathies (MFM) are chronic muscle diseases characterized by protein aggregate accumulation and muscle fiber damage.
- A subset of MFM is linked to heterozygous mutations in the filamin C (FLNC) gene, leading to progressive muscle weakness and structural changes.
Purpose of the Study:
- To deeply investigate the pathogenicity of two new truncating FLNC variants (p.Q1662X and p.Y2704X).
- To evaluate the distinct effects of these variants on FLNC stability, distribution, and protein quality system (PQS) pathways.
Main Methods:
- Characterization of two novel FLNC variants (p.Q1662X and p.Y2704X) in patients with myopathy.
- Assessment of FLNC stability, distribution, and impact on protein quality systems, including the ubiquitin-proteasome system (UPS) and chaperone-assisted selective autophagy (CASA).
Main Results:
- Both p.Q1662X and p.Y2704X variants cause slowly progressive adult-onset myopathy with characteristic muscle alterations and protein aggregates.
- p.Q1662X leads to FLNC haploinsufficiency, while p.Y2704X results in dominant-negative FLNC accumulation.
- Distinct PQS alterations were observed: p.Q1662X increased UPS and CASA gene expression, whereas p.Y2704X increased UPS activation and autophagic buildup proteins.
Conclusions:
- Truncating FLNC variants can have diverse pathogenetic consequences and impair PQS function through varied mechanisms and to different degrees.
- Further studies with larger patient cohorts are required to validate these findings on FLNC-related myopathies.
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