title: Distal myopathy with upper limb predominance caused by filamin C haploinsufficiency.
abstract: OBJECTIVE
  In this study, we investigated the detailed clinical findings and underlying genetic defect in 3 presumably related Bulgarian families displaying dominantly transmitted adult onset distal myopathy with upper limb predominance.
  
  
  METHODS
  We performed neurologic, electrophysiologic, radiologic, and histopathologic analyses of 13 patients and 13 at-risk but asymptomatic individuals from 3 generations. Genome-wide parametric linkage analysis was followed by bidirectional sequencing of the filamin C (FLNC) gene. We characterized the identified nonsense mutation at cDNA and protein level.
  
  
  RESULTS
  Based on clinical findings, no known myopathy subtype was implicated in our distal myopathy patients. Light microscopic analysis of affected muscle tissue showed no specific hallmarks; however, the electron microscopy revealed changes compatible with myofibrillar myopathy. Linkage studies delineated a 9.76 Mb region on chromosome 7q22.1-q35 containing filamin C (FLNC), a gene previously associated with myofibrillar myopathy. Mutation analysis revealed a novel c.5160delC frameshift deletion in all patients of the 3 families. The mutation results in a premature stop codon (p.Phe1720LeufsX63) that triggers nonsense-mediated mRNA decay. FLNC transcript levels were reduced in muscle and lymphoblast cells from affected subjects and partial loss of FLNC in muscle tissue was confirmed by protein analysis.
  
  
  CONCLUSIONS
  The FLNC mutation that we identified is distinct in terms of the associated phenotype, muscle morphology, and underlying molecular mechanism, thus extending the currently recognized clinical and genetic spectrum of filaminopathies. We conclude that filamin C is a dosage-sensitive gene and that FLNC haploinsufficiency can cause a specific type of myopathy in humans.
authors: Department of Neurology, Medical University-Sofia, Sofia, Bulgaria.
authors: V
authors: V
authors: Guergueltcheva
authors: K
authors: K
authors: Peeters
authors: J
authors: J
authors: Baets
authors: C
authors: C
authors: Ceuterick-de Groote
authors: J J
authors: JJ
authors: Martin
authors: A
authors: A
authors: Suls
authors: E
authors: E
authors: De Vriendt
authors: V
authors: V
authors: Mihaylova
authors: T
authors: T
authors: Chamova
authors: L
authors: L
authors: Almeida-Souza
authors: E
authors: E
authors: Ydens
authors: C
authors: C
authors: Tzekov
authors: G
authors: G
authors: Hadjidekov
authors: M
authors: M
authors: Gospodinova
authors: K
authors: K
authors: Storm
authors: E
authors: E
authors: Reyniers
authors: S
authors: S
authors: Bichev
authors: P F M
authors: PF
authors: van der Ven
authors: D O
authors: DO
authors: Fürst
authors: V
authors: V
authors: Mitev
authors: H
authors: H
authors: Lochmüller
authors: V
authors: V
authors: Timmerman
authors: I
authors: I
authors: Tournev
authors: P
authors: P
authors: De Jonghe
authors: A
authors: A
authors: Jordanova
mesh_terms: D000328:Adult; D002031:Bulgaria; D003285:Contractile Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis; D049310:Distal Myopathies / Q000235:genetics*; D005260:Female; D064448:Filamins; D008040:Genetic Linkage; D055106:Genome-Wide Association Study; D005838:Genotype; D057895:Haploinsufficiency / Q000235:genetics*; D006801:Humans; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics*; D008875:Middle Aged; D010375:Pedigree
chemical_list: D003285:Contractile Proteins; C578661:FLNC protein, human; D064448:Filamins; D008840:Microfilament Proteins