1998 Fiscal Year Final Research Report Summary
Molecular mechanism of HCM caused by mutation in the cardiac TnT gene.
| Project/Area Number |
09670771
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Circulatory organs internal medicine
|
|---|
| Research Institution | KURUME UNIVERSITY |
|---|
Principal Investigator |
NAKATA Masashi Kurume University, School of Medicine, Assistant Professor, 医学部, 講師 (70180304)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
NAKAURA Hiroyuki Kurume University, School of Medicine, Instructor, 医学部, 助手 (50279171)
IWAMI Gensho Kurume University, School of Medicine, Assistant Professor, 医学部, 講師 (90203405)
NISHI Hirofumi Kurume University, School of Medicine, Assistant Professor, 医学部, 講師 (60189248)
|
|---|
| Project Period (FY) |
1997 – 1998
|
| Keywords | Hypertrophic cardiomyopathy / Troponin T / Skinned fiber / Splice-donor site mutation / Calcium sensitivity |
|---|
| Research Abstract |
A splice donor site mutation in intron 15 of the cardiac troponin T (TnT) gene has been shown to cause familial hypertrophic cardiomyopathy (HCM) and the translation of the aberrant mRNAs resulting from this mutation is expected to produce two truncated mutant molecules lacking carboxyl terminus to different extent. In this study, wild-type and two truncated human cardiac TnTs were expressed in E.coli and directly exchanged into rabbit permeabilized cardiac muscle fibers to determinine the functional consequence of this HCM-causing mutation. The skinned fibers exchanged with short truncated TnT generated a slightly lower Ca^<2+>-activated maximum force compared to the fibers exchanged with wild-type TnT, which is qualitatively consistent with the finding on a transfected quail skeletal myotube expressing this mutant TnT.On the other hand, long truncated TnT had no effect on the maximum force-generating capacity. Both these two truncated human cardiac TnTs conferred a lower cooperativity and high Ca^<2+> sensitivity on the Ca^<2+> activation of skkined cardiac muscle than wild-type TnT.The results provide evidence that an increased Ca^<2+> sensitivity and decreased cooperativity in the activation of cardiac myofilament may be involved in the pathogenesis of HCM caused by this splice donor site mutation in the cardiac TnT gene.
|
