Severe familial left ventricular non-compaction cardiomyopathy due to a novel troponin T (TNNT2) mutation.
OBJECTIVE
Left ventricular non-compaction (LVNC) is caused by mutations in multiple genes. It is still unclear whether LVNC is the primary determinant of cardiomyopathy or rather a secondary phenomenon with intrinsic cardiomyocyte dysfunction being the actual cause of the disease. Here, we describe a family with LVNC due to a novel missense mutation, pE96K, in the cardiac troponin T gene (TNNT2).


RESULTS
The novel mutation was identified in the index patient and all affected relatives, but not in 430 healthy control individuals. Mutations in known LVNC-associated genes were excluded. To investigate the pathophysiological implications of the mutation, we generated transgenic mice expressing human wild-type cTNT (hcTNT) or a human troponin T harbouring the pE96K mutation (mut cTNT). Animals were characterized by echocardiography, histology, and gene expression analysis. Mut cTNT mice displayed an impaired left ventricular function and induction of marker genes of heart failure. Remarkably, left ventricular non-compaction was not observed.


CONCLUSIONS
Familial co-segregation and the cardiomyopathy phenotype of mut cTNT mice strongly support a causal relationship of the pE96K mutation and disease in our index patient. In addition, our data suggest that a non-compaction phenotype is not required for the development of cardiomyopathy in this specific TNNT2 mutation leading to LVNC.
Luedde
Mark
M
Department of Internal Medicine III, University of Heidelberg, 69120 Heidelberg, Germany.
Ehlermann
Philipp
P
Weichenhan
Dieter
D
Will
Rainer
R
Zeller
Raphael
R
Rupp
Stefan
S
Müller
Andreas
A
Steen
Henning
H
Ivandic
Boris T
BT
Ulmer
Herbert E
HE
Kern
Michael
M
Katus
Hugo A
HA
Frey
Norbert
N
D000818:Animals; D001706:Biopsy; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D018618:Echocardiography, Doppler, Color; D005091:Exons; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D056830:Isolated Noncompaction of the Ventricular Myocardium / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D019028:Magnetic Resonance Imaging, Cine; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D020125:Mutation, Missense; D009200:Myocardial Contraction / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D012720:Severity of Illness Index; D013318:Stroke Volume / Q000235:genetics; D020107:Troponin T / Q000235:genetics*; D018487:Ventricular Dysfunction, Left / Q000235:genetics / Q000503:physiopathology; D055815:Young Adult
C545568:TNNT2 protein, human; D020107:Troponin T