Identification of a novel TPM1 mutation in a family with left ventricular noncompaction and sudden death.
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. We screened 4 genes (TAZ, LDB3, DTNA and TPM1) in 51 patients with LVNC for mutations by polymerase chain reaction and direct DNA sequencing. A novel missense substitution in exon 1 of TPM1 (c.109A>G: p.Lys37Glu) was identified in three affected members of a family with isolated LVNC. 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 and 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. Screening of the proband and her mother for variants in other sarcomeric protein-encoding candidate genes, MYH7, MYBPC3, TNNT2, TNNI3, ACTC, MYL2, and MYL3, did not identify any other non-synonymous variants or variants in splice donor-acceptor sequences that were potentially disease causing. We conclude TPM1 is a potential candidate disease-causing gene for isolated LVNC, especially in patients experiencing sudden death.
Chang
Bo
B
Department of Pediatrics, University of Toyama, 2630 Sugitani, Toyama, Japan.
Nishizawa
Tsutomu
T
Furutani
Michiko
M
Fujiki
Akira
A
Tani
Masanao
M
Kawaguchi
Makoto
M
Ibuki
Keijiro
K
Hirono
Keiichi
K
Taneichi
Hiromichi
H
Uese
Keiichiro
K
Onuma
Yoshiko
Y
Bowles
Neil E
NE
Ichida
Fukiko
F
Inoue
Hiroshi
H
Matsuoka
Rumiko
R
Miyawaki
Toshio
T
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000328:Adult; D044466:Asian People / Q000235:genetics; D002648:Child; D016757:Death, Sudden, Cardiac; D049029:Dystrophin-Associated Proteins / Q000235:genetics; D004562:Electrocardiography; D005260:Female; D005838:Genotype; D006352:Heart Ventricles / Q000000981:diagnostic imaging / Q000473:pathology*; D006801:Humans; D056830:Isolated Noncompaction of the Ventricular Myocardium / Q000235:genetics* / Q000473:pathology; D060588:LIM Domain Proteins; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009479:Neuropeptides / Q000235:genetics; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D014335:Tropomyosin / Q000235:genetics*; D014463:Ultrasonography; D055815:Young Adult
D048868:Adaptor Proteins, Signal Transducing; C490915:DTNA protein, human; D049029:Dystrophin-Associated Proteins; C120696:LDB3 protein, human; D060588:LIM Domain Proteins; D009479:Neuropeptides; C490775:TPM1 protein, human; D014335:Tropomyosin