Abstract 10226: Identification of A Novel TPM1 Mutation in Left Ventricular Noncompaction and Sudden Death
Background: Left ventricular noncompaction (LVNC) is a cardiomyopathy morphologically characterized by 2-layered myocardium, numerous prominent trabeculations, and deep intertrabecular recesses communicating with the left ventricular cavity. The purpose of this study was to investigate patients with LVNC for possible disease causing mutations.
Methods and Results: We screened 11 genes in 51 patients with LVNC for mutations by polymerase chain reaction and direct DNA sequencing. Six of these genes encoded proteins previously associated with LVNC (LIM domain binding protein 3, α-dystrobrevin, tafazzin, β-myosin heavy chain, α-cardiac actin and cardiac troponin T), while the remainder encoded sarcomeric proteins (myosin binding protein 3, cardiac toponin I, cardiac regulatory myosin light chain, cardic essential myosin light chain and α-tropomyosin (TPM1)) associated with other inherited forms of cardiomyopathy. A novel missense substitution in exon 1 of TPM1 (c.109A>G: p.Lys37Glu) was identified in the proband of one Japanese family with isolated LVNC and sudden death. The same variant was identified in each of the affected living members of the family (the proband's mother and maternal aunt). The substitution brings about a change in amino acid charge at a highly conserved residue and could result in aberrant mRNA splicing. This variant was not identified in 200 normal control samples. Pathologic analysis of a right ventricular myocardial specimen from the proband's maternal aunt revealed endocardial or subendocardial fibrosis with prominent elastin deposition, as well as the presence of adipose tissue between muscle layers, pathologic changes that are distinct from those seen in patients with HCM or DCM.
Conclusions: We conclude TPM1 is a potential candidate disease-causing gene for isolated LVNC, especially in patients experiencing sudden death.
- © 2010 by American Heart Association, Inc.