PMID- 10449439
OWN - NLM
STAT- MEDLINE
DCOM- 19990914
LR  - 20181113
IS  - 0021-9738 (Print)
IS  - 0021-9738 (Linking)
VI  - 104
IP  - 4
DP  - 1999 Aug
TI  - Cardiac troponin T mutations result in allele-specific phenotypes in a mouse
      model for hypertrophic cardiomyopathy.
PG  - 469-81
AB  - Multiple mutations in cardiac troponin T (cTnT) can cause familial hypertrophic
      cardiomyopathy (FHC). Patients with cTnT mutations generally exhibit mild or no
      ventricular hypertrophy, yet demonstrate a high frequency of early sudden death. 
      To understand the functional basis of these phenotypes, we created transgenic
      mouse lines expressing 30%, 67%, and 92% of their total cTnT as a missense (R92Q)
      allele analogous to one found in FHC. Similar to a mouse FHC model expressing a
      truncated cTnT protein, the left ventricles of all R92Q lines are smaller than
      those of wild-type. In striking contrast to truncation mice, however, the R92Q
      hearts demonstrate significant induction of atrial natriuretic factor and
      beta-myosin heavy chain transcripts, interstitial fibrosis, and mitochondrial
      pathology. Isolated cardiac myocytes from R92Q mice have increased basal
      sarcomeric activation, impaired relaxation, and shorter sarcomere lengths.
      Isolated working heart data are consistent, showing hypercontractility and
      diastolic dysfunction, both of which are common findings in patients with FHC.
      These mice represent the first disease model to exhibit hypercontractility, as
      well as a unique model system for exploring the cellular pathogenesis of FHC. The
      distinct phenotypes of mice with different TnT alleles suggest that the clinical 
      heterogeneity of FHC is at least partially due to allele-specific mechanisms.
FAU - Tardiff, J C
AU  - Tardiff JC
AD  - Department of Molecular, Cellular and Developmental Biology, University of
      Colorado, Boulder, Colorado 80309, USA.
FAU - Hewett, T E
AU  - Hewett TE
FAU - Palmer, B M
AU  - Palmer BM
FAU - Olsson, C
AU  - Olsson C
FAU - Factor, S M
AU  - Factor SM
FAU - Moore, R L
AU  - Moore RL
FAU - Robbins, J
AU  - Robbins J
FAU - Leinwand, L A
AU  - Leinwand LA
LA  - eng
GR  - HL-060546/HL/NHLBI NIH HHS/United States
GR  - HL-50560/HL/NHLBI NIH HHS/United States
GR  - R37 HL050560/HL/NHLBI NIH HHS/United States
GR  - R01 HL040306/HL/NHLBI NIH HHS/United States
GR  - HL-40306/HL/NHLBI NIH HHS/United States
GR  - R01 HL050560/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Clin Invest
JT  - The Journal of clinical investigation
JID - 7802877
RN  - 0 (DNA Primers)
RN  - 0 (Troponin T)
RN  - 85637-73-6 (Atrial Natriuretic Factor)
RN  - EC 3.6.4.1 (Myosin Heavy Chains)
SB  - AIM
SB  - IM
MH  - Alleles
MH  - Animals
MH  - Atrial Natriuretic Factor/genetics
MH  - Base Sequence
MH  - Cardiomyopathy, Hypertrophic/*genetics/pathology/physiopathology
MH  - Cell Size
MH  - DNA Primers/genetics
MH  - Disease Models, Animal
MH  - Heart Ventricles/pathology
MH  - Humans
MH  - In Vitro Techniques
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Inbred CBA
MH  - Mice, Transgenic
MH  - Microscopy, Electron
MH  - *Mutation, Missense
MH  - Myocardial Contraction
MH  - Myosin Heavy Chains/genetics
MH  - Phenotype
MH  - Sarcomeres/ultrastructure
MH  - Troponin T/*genetics
PMC - PMC408522
EDAT- 1999/08/17 00:00
MHDA- 1999/08/17 00:01
CRDT- 1999/08/17 00:00
PHST- 1999/08/17 00:00 [pubmed]
PHST- 1999/08/17 00:01 [medline]
PHST- 1999/08/17 00:00 [entrez]
AID - 10.1172/JCI6067 [doi]
PST - ppublish
SO  - J Clin Invest. 1999 Aug;104(4):469-81. doi: 10.1172/JCI6067.