Mutations in filamin C cause a new form of familial hypertrophic cardiomyopathy

Rafael Valdés-Mas, Ana Gutiérrez-Fernández, Juan Gómez, Eliecer Coto, Aurora Astudillo, Diana A. Puente, Julián R. Reguero, Victoria Álvarez, César Morís, Diego León, María Martín, Xose S Puente () and Carlos López-Otín ()
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Rafael Valdés-Mas: Facultad de Medicina, Instituto Universitario de Oncología-IUOPA, Universidad de Oviedo
Ana Gutiérrez-Fernández: Facultad de Medicina, Instituto Universitario de Oncología-IUOPA, Universidad de Oviedo
Juan Gómez: Genética Molecular, Red de Investigación Renal (REDINREN)
Eliecer Coto: Genética Molecular, Red de Investigación Renal (REDINREN)
Aurora Astudillo: Servicio de Anatomía Patológica, Hospital Universitario Central de Asturias
Diana A. Puente: Facultad de Medicina, Instituto Universitario de Oncología-IUOPA, Universidad de Oviedo
Julián R. Reguero: Servicio de Cardiología, Fundación Asturcor, Hospital Universitario Central de Asturias
Victoria Álvarez: Genética Molecular, Red de Investigación Renal (REDINREN)
César Morís: Universidad de Oviedo
Diego León: Servicio de Cardiología, Fundación Asturcor, Hospital Universitario Central de Asturias
María Martín: Servicio de Cardiología, Fundación Asturcor, Hospital Universitario Central de Asturias
Xose S Puente: Facultad de Medicina, Instituto Universitario de Oncología-IUOPA, Universidad de Oviedo
Carlos López-Otín: Facultad de Medicina, Instituto Universitario de Oncología-IUOPA, Universidad de Oviedo

Nature Communications, 2014, vol. 5, issue 1, 1-9

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms6326

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