title: Cardiac arrhythmia and late-onset muscle weakness caused by a myofibrillar myopathy with unusual histopathological features due to a novel missense mutation in FLNC.
abstract: Myofibrillar myopathies (MFM) are mostly adult-onset diseases characterized by progressive morphological alterations of the muscle fibers beginning in the Z-disk and the presence of protein aggregates in the sarcoplasm. They are mostly caused by mutations in different genes that encode Z-disk proteins, including DES, CRYAB, LDB3, MYOT, FLNC and BAG3. A large family of French origin, presenting an autosomal dominant pattern, characterized by cardiac arrhythmia associated to late-onset muscle weakness, was evaluated to clarify clinical, morphological and genetic diagnosis. Muscle weakness began during adult life (over 30 years of age), and had a proximal distribution. Histology showed clear signs of a myofibrillar myopathy, but with unusual, large inclusions. Subsequently, genetic testing was performed in MFM genes available for screening at the time of clinical/histological diagnosis, and desmin (DES), αB-crystallin (CRYAB), myotilin (MYOT) and ZASP (LDB3), were excluded. LMNA gene screening found the p.R296C variant which did not co-segregate with the disease. Genome wide scan revealed linkage to 7q.32, containing the FLNC gene. FLNC direct sequencing revealed a heterozygous c.3646T>A p.Tyr1216Asn change, co-segregating with the disease, in a highly conserved amino acid of the protein. Normal filamin C levels were detected by Western-blot analysis in patient muscle biopsies and expression of the mutant protein in NIH3T3 showed filamin C aggregates. This is an original FLNC mutation in a MFM family with an atypical clinical and histopathological presentation, given the presence of significantly focal lesions and prominent sarcoplasmic masses in muscle biopsies and the constant heart involvement preceding significantly the onset of the myopathy. Though a rare etiology, FLNC gene should not be excluded in early-onset arrhythmia, even in the absence of myopathy, which occurs later in the disease course.
authors.affiliation: Sorbonne universités, UPMC Paris 06, center of research in myology, Inserm UMRS974, CNRS FRE3617, 75013 Paris, France.
authors.forename: D
authors.initials: D
authors.lastname: Avila-Smirnow
authors.affiliation: Sorbonne universités, UPMC Paris 06, center of research in myology, Inserm UMRS974, CNRS FRE3617, 75013 Paris, France.
authors.forename: L
authors.initials: L
authors.lastname: Gueneau
authors.affiliation: Sorbonne Paris Cité, université Paris Diderot, CNRS, unité de biologie fonctionnelle et adaptative, UMR 8251, 75013 Paris, France.
authors.forename: S
authors.initials: S
authors.lastname: Batonnet-Pichon
authors.affiliation: Sorbonne Paris Cité, université Paris Diderot, CNRS, unité de biologie fonctionnelle et adaptative, UMR 8251, 75013 Paris, France.
authors.forename: F
authors.initials: F
authors.lastname: Delort
authors.affiliation: AP-HP, groupe hospitalier Pitié-Salpêtrière, institut de myologie, centre de référence de pathologie neuromusculaire Paris-Est, 47-83, boulevard de l'Hôpital, 75013 Paris, France.
authors.forename: H-M
authors.initials: HM
authors.lastname: Bécane
authors.affiliation: Groupe hospitalier Pitié-Salpêtrière, association institut de myologie, unité de morphologie neuromusculaire, 75013 Paris, France.
authors.forename: K
authors.initials: K
authors.lastname: Claeys
authors.affiliation: Sorbonne universités, UPMC Paris 06, center of research in myology, Inserm UMRS974, CNRS FRE3617, 75013 Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Beuvin
authors.affiliation: Sorbonne universités, UPMC Paris 06, center of research in myology, Inserm UMRS974, CNRS FRE3617, 75013 Paris, France.
authors.forename: B
authors.initials: B
authors.lastname: Goudeau
authors.affiliation: GH Necker Enfants-Malades, université Paris Descartes, faculté de médecine, biostatistique et informatique médicale, EA 4067, 75015 Paris, France.
authors.forename: J-P
authors.initials: JP
authors.lastname: Jais
authors.affiliation: Sorbonne universités, UPMC Paris 06, center of research in myology, Inserm UMRS974, CNRS FRE3617, 75013 Paris, France.
authors.forename: I
authors.initials: I
authors.lastname: Nelson
authors.affiliation: AP-HP, groupe hospitalier Pitié-Salpêtrière, service de biochimie métabolique, U.F. cardiogénétique et myogénétique, 75013 Paris, France.
authors.forename: P
authors.initials: P
authors.lastname: Richard
authors.affiliation: Sorbonne universités, UPMC Paris 06, center of research in myology, Inserm UMRS974, CNRS FRE3617, 75013 Paris, France; AP-HP, groupe hospitalier Pitié-Salpêtrière, institut de myologie, centre de référence de pathologie neuromusculaire Paris-Est, 47-83, boulevard de l'Hôpital, 75013 Paris, France.
authors.forename: R
authors.initials: R
authors.lastname: Ben Yaou
authors.affiliation: Sorbonne universités, UPMC Paris 06, center of research in myology, Inserm UMRS974, CNRS FRE3617, 75013 Paris, France; Groupe hospitalier Pitié-Salpêtrière, association institut de myologie, unité de morphologie neuromusculaire, 75013 Paris, France.
authors.forename: N B
authors.initials: NB
authors.lastname: Romero
authors.affiliation: Sorbonne universités, UPMC Paris 06, center of research in myology, Inserm UMRS974, CNRS FRE3617, 75013 Paris, France; AP-HP, groupe hospitalier Pitié-Salpêtrière, institut de myologie, centre de référence de pathologie neuromusculaire Paris-Est, 47-83, boulevard de l'Hôpital, 75013 Paris, France; AP-HP, groupe hospitalier Cochin-Broca-Hôtel Dieu, service de cardiologie, 75013 Paris, France.
authors.forename: K
authors.initials: K
authors.lastname: Wahbi
authors.affiliation: CHU de la Milétrie, service de neurologie, 86021 Poitiers, France.
authors.forename: S
authors.initials: S
authors.lastname: Mathis
authors.affiliation: Sorbonne universités, UPMC Paris 06, center of research in myology, Inserm UMRS974, CNRS FRE3617, 75013 Paris, France; AP-HP, groupe hospitalier Pitié-Salpêtrière, institut de myologie, centre de référence de pathologie neuromusculaire Paris-Est, 47-83, boulevard de l'Hôpital, 75013 Paris, France.
authors.forename: T
authors.initials: T
authors.lastname: Voit
authors.affiliation: University of Bonn, institute for cell biology, department of molecular cell biology, Bonn, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Furst
authors.affiliation: University of Bonn, institute for cell biology, department of molecular cell biology, Bonn, Germany.
authors.forename: P
authors.initials: P
authors.lastname: van der Ven
authors.affiliation: CHU de la Milétrie, service de neurologie, 86021 Poitiers, France.
authors.forename: R
authors.initials: R
authors.lastname: Gil
authors.affiliation: Sorbonne Paris Cité, université Paris Diderot, CNRS, unité de biologie fonctionnelle et adaptative, UMR 8251, 75013 Paris, France.
authors.forename: P
authors.initials: P
authors.lastname: Vicart
authors.affiliation: Groupe hospitalier Pitié-Salpêtrière, association institut de myologie, unité de morphologie neuromusculaire, 75013 Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Fardeau
authors.affiliation: Sorbonne universités, UPMC Paris 06, center of research in myology, Inserm UMRS974, CNRS FRE3617, 75013 Paris, France.
authors.forename: G
authors.initials: G
authors.lastname: Bonne
authors.affiliation: AP-HP, groupe hospitalier Pitié-Salpêtrière, institut de myologie, centre de référence de pathologie neuromusculaire Paris-Est, 47-83, boulevard de l'Hôpital, 75013 Paris, France. Electronic address: anthony.behin@aphp.fr.
authors.forename: A
authors.initials: A
authors.lastname: Behin
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000595:Amino Acid Sequence; D001145:Arrhythmias, Cardiac / Q000209:etiology*; D004252:DNA Mutational Analysis; D005190:Family; D005260:Female; D064448:Filamins / Q000235:genetics*; D015894:Genome, Human; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D018908:Muscle Weakness / Q000209:etiology*; D009135:Muscular Diseases / Q000150:complications* / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics*; D009210:Myofibrils / Q000473:pathology; D010375:Pedigree; D055815:Young Adult
chemical_list: C578661:FLNC protein, human; D064448:Filamins
keywords: Functional anomalies; Genome wide scan; Morphology; Myofibrillar myopathies; NIH 3T3; Western blots