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

Authors:
Valdés-Mas R, Gutiérrez-Fernández A, Gómez J, Coto E, Astudillo A, Puente DA, Reguero JR, Alvarez V, Morís C, León D, Martín M, Puente XS, López-Otín C.
In:
Source: Nat Commun.
Publication Date: (2014)
Issue: 5: 5326
Research Area:
Neurobiology
Cells used in publication:
Cardiomyocyte (R-CM), rat
Species: rat
Tissue Origin: heart
H9c2(2-1)
Species: rat
Tissue Origin: heart
Platform:
4D-Nucleofector™ X-Unit
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.