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: 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, Carlos López-Otín
• Journal: Nature communications (Nat Commun) Vol. 5 Pg. 5326 (Oct 29 2014) ISSN: 2041-1723 [Electronic] England
• PMID: 25351925 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Filamins

Topics

• Amino Acid Sequence
• Animals
• Base Sequence
• Cardiomyopathy, Hypertrophic, Familial (genetics)
• Exome (genetics)
• Female
• Filamins (chemistry, genetics)
• Humans
• Male
• Middle Aged
• Molecular Sequence Data
• Mutation (genetics)
• Myocardium (pathology, ultrastructure)
• Myocytes, Cardiac (metabolism, pathology)
• Pedigree
• Rats
• Sequence Analysis, DNA
• Young Adult