Titin mutations as the molecular basis for dilated cardiomyopathy

Biochemical and Biophysical Research Communications
Manatsu Itoh-SatohAkinori Kimura

Abstract

Dilated cardiomyopathy (DCM) is a heterogeneous cardiac disease characterized by ventricular dilatation and systolic dysfunction. Recent genetic studies have revealed that mutations in genes for cardiac sarcomere components lead to DCM. The cardiac sarcomere consists of thick and thin filaments and a giant protein, titin. Because one of the loci of familial DCM was mapped to the region of the titin gene, we searched for titin mutations in the patients and identified four possible disease-associated mutations. Two mutations, Val54Met and Ala743Val, were found in the Z-line region of titin and decreased binding affinities of titin to Z-line proteins T-cap/telethonin and alpha-actinin, respectively, in yeast two-hybrid assays. The other two mutations were found in the cardiac-specific N2-B region of titin and one of them was a nonsense mutation, Glu4053ter, presumably encoding for a truncated nonfunctional molecule. These observations suggest that titin mutations may cause DCM in a subset of the patients.

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Related Concepts

Cardiomyopathy, Familial Idiopathic
Yeast Two-Hybrid System Techniques
Sarcomeres
Mutation, Nonsense
TCAP gene
Tertiary Protein Structure
TTN gene
Protein KINASE
Z Line
Dilated Cardiomyopathy Pathway

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