title: Mutations in filamin C cause a new form of familial hypertrophic cardiomyopathy.
abstract: Mutations in different genes encoding sarcomeric proteins are responsible for 50-60% of familial cases of hypertrophic cardiomyopathy (HCM); however, the genetic alterations causing the disease in one-third of patients are currently unknown. Here we describe a case with familial HCM of unknown cause. Whole-exome sequencing reveals a variant in the gene encoding the sarcomeric protein filamin C (p.A1539T) that segregates with the disease in this family. Sequencing of 92 HCM cases identifies seven additional variants segregating with the disease in eight families. Patients with FLNC mutations show marked sarcomeric abnormalities in cardiac muscle, and functional analysis reveals that expression of these FLNC variants resulted in the formation of large filamin C aggregates. Clinical studies indicate that FLNC-mutated patients have higher incidence of sudden cardiac death. On the basis of these findings, we conclude that mutations in the gene encoding the sarcomeric protein filamin C cause a new form of familial HMC.
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología-IUOPA, Universidad de Oviedo, 33006 Oviedo, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Valdés-Mas
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología-IUOPA, Universidad de Oviedo, 33006 Oviedo, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Gutiérrez-Fernández
authors.affiliation: Genética Molecular, Red de Investigación Renal (REDINREN), 33006 Oviedo, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Gómez
authors.affiliation: 1] Genética Molecular, Red de Investigación Renal (REDINREN), 33006 Oviedo, Spain [2] Departamento de Medicina, Universidad de Oviedo, 33006 Oviedo, Spain.
authors.forename: Eliecer
authors.initials: E
authors.lastname: Coto
authors.affiliation: Servicio de Anatomía Patológica, Hospital Universitario Central de Asturias, 33006 Oviedo, Spain.
authors.forename: Aurora
authors.initials: A
authors.lastname: Astudillo
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología-IUOPA, Universidad de Oviedo, 33006 Oviedo, Spain.
authors.forename: Diana A
authors.initials: DA
authors.lastname: Puente
authors.affiliation: Servicio de Cardiología, Fundación Asturcor, Hospital Universitario Central de Asturias, 33006 Oviedo, Spain.
authors.forename: Julián R
authors.initials: JR
authors.lastname: Reguero
authors.affiliation: Genética Molecular, Red de Investigación Renal (REDINREN), 33006 Oviedo, Spain.
authors.forename: Victoria
authors.initials: V
authors.lastname: Álvarez
authors.affiliation: 1] Departamento de Medicina, Universidad de Oviedo, 33006 Oviedo, Spain [2] Servicio de Cardiología, Fundación Asturcor, Hospital Universitario Central de Asturias, 33006 Oviedo, Spain.
authors.forename: César
authors.initials: C
authors.lastname: Morís
authors.affiliation: Servicio de Cardiología, Fundación Asturcor, Hospital Universitario Central de Asturias, 33006 Oviedo, Spain.
authors.forename: Diego
authors.initials: D
authors.lastname: León
authors.affiliation: Servicio de Cardiología, Fundación Asturcor, Hospital Universitario Central de Asturias, 33006 Oviedo, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Martín
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología-IUOPA, Universidad de Oviedo, 33006 Oviedo, Spain.
authors.forename: Xose S
authors.initials: XS
authors.lastname: Puente
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología-IUOPA, Universidad de Oviedo, 33006 Oviedo, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: López-Otín
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005260:Female; D064448:Filamins / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009206:Myocardium / Q000473:pathology / Q000648:ultrastructure; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D010375:Pedigree; D051381:Rats; D017422:Sequence Analysis, DNA; D055815:Young Adult
chemical_list: D064448:Filamins