title: A novel titin mutation in adult-onset familial dilated cardiomyopathy.
abstract: Familial dilated cardiomyopathy is a major cause of advanced heart failure and heart transplantation. In most families, the disease-causing mutation is unknown, and relatives should therefore undergo periodic screening to facilitate early diagnosis and therapy. In the present study, we describe a novel titin truncation mutation causing adult-onset familial dilated cardiomyopathy in an Israeli Arab family. The family members underwent physical examination, electrocardiography, and Doppler echocardiography. Linkage to candidate loci was performed, followed by gene sequencing. We identified 13 clinically affected family members (8 men and 5 women, mean age 47 ± 12 years). Compared with their healthy first-degree relatives, the affected relatives had a larger end-diastolic left ventricular dimension (60 ± 10 vs 49 ± 4 mm, p <0.001), lower ejection fraction (43 ± 11% vs 60 ± 6%, p <0.001), and markedly higher end-systolic volume indexes but no difference in wall thickness or diastolic function. The linkage studies or direct sequencing excluded LMNA, MYH7, TNNT2, TNNI3, SCN5A, DES, SGCD, ACTC, PLN, and MYH6 but established linkage to the TTN locus at chromosome 2q31, yielding a maximum (2-point) LOD score of 3.44. Sequence analysis identified an insertion (c.58880insA), causing protein truncation after 19,628 amino acids (p.S19628IfsX1). No founder effect was found among the Israeli Arabs. In conclusion, titin is a giant protein with a key role in sarcomere assembly, force transmission, and maintenance of resting tension. Although some mutations result in skeletal myopathy, others cause isolated, maturity-onset cardiomyopathy.
authors.affiliation: Heart Failure Service and Heart Institute, Sheba Medical Center, Tel Hashomer, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Guy
authors.initials: G
authors.lastname: Yoskovitz
authors.forename: Yael
authors.initials: Y
authors.lastname: Peled
authors.forename: Michael
authors.initials: M
authors.lastname: Gramlich
authors.forename: Hadas
authors.initials: H
authors.lastname: Lahat
authors.forename: Heike
authors.initials: H
authors.lastname: Resnik-Wolf
authors.forename: Micha S
authors.initials: MS
authors.lastname: Feinberg
authors.forename: Arnon
authors.initials: A
authors.lastname: Afek
authors.forename: Elon
authors.initials: E
authors.lastname: Pras
authors.forename: Michael
authors.initials: M
authors.lastname: Arad
authors.forename: Brenda
authors.initials: B
authors.lastname: Gerull
authors.forename: Dov
authors.initials: D
authors.lastname: Freimark
mesh_terms: D000328:Adult; D018912:Arabs / Q000235:genetics; D002311:Cardiomyopathy, Dilated / Q000235:genetics*; D002889:Chromosomes, Human, Pair 2; D064211:Connectin; D005260:Female; D016368:Frameshift Mutation; D008040:Genetic Linkage; D006239:Haplotypes; D006801:Humans; D007557:Israel; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics*; D010375:Pedigree; D011494:Protein Kinases / Q000235:genetics*
chemical_list: D064211:Connectin; D009124:Muscle Proteins; C577285:TTN protein, human; D011494:Protein Kinases