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Filamin C (FLNC) encodes an actin-crosslinking protein critical for sarcomeric integrity in skeletal muscle. Heterozygous variants in FLNC are established causes of autosomal dominant myofibrillar myopathy 5 (Myofibrillar Myopathy 5), characterized by progressive muscle weakness and intracellular protein aggregates.
Autosomal dominant inheritance is supported by segregation of FLNC variants in at least three unrelated families with >20 affected individuals. In a large Chinese kindred, an in-frame 18-nt deletion/6-nt insertion in exon 18 (c.2695_2712delinsGTTTGT causing p.Lys899_Glu904delinsValCys) co-segregated with myopathy and chronic diarrhea (HP:0002028) (PMID:20417099). Other pedigrees harbor truncating and missense mutations in Ig-like and dimerization domains.
Reported variants include truncating alleles (e.g., c.8130G>A (p.Trp2710Ter)), in-frame indels, and missense changes clustering in rod and dimerization domains. These variants show co-segregation with myopathic features and typical myofibrillar pathology across kindreds.
Biochemical and cell-culture studies demonstrate that FLNC truncations and rod-domain mutations destabilize the dimerization domain, promote proteolysis, and lead to aggregates in muscle fibers (PMID:17412757). Knock-in mouse models of p.Trp2710X recapitulate protein aggregation and mechanosensing defects, confirming a dominant-negative mechanism.
No substantive refuting or alternative gene associations for MFM 5 have been reported to date.
Collectively, genetic and experimental data support a Strong FLNC–Myofibrillar Myopathy 5 association. FLNC testing should be included in diagnostic myopathy panels, and identification of pathogenic variants informs prognosis and familial risk.
Key Take-home: Autosomal dominant FLNC variants induce toxic protein aggregation and misfolding, underpinning myofibrillar myopathy 5 and warrant inclusion in genetic diagnostics.
Gene–Disease AssociationStrongThree unrelated families with autosomal dominant FLNC variants in >20 probands, multi-family segregation, concordant functional data Genetic EvidenceStrongMultiple FLNC truncating and missense variants co-segregate with myofibrillar myopathy across kindreds; reached genetic evidence cap Functional EvidenceModerateBiochemical and cellular models show mutant FLNc misfolding, aggregation, and impaired dimerization; mouse knock-in replicates pathology |