Principal investigators
Funding
Research
Our major research focus is on the molecular
genetic bases of cardiovascular diseases.
This includes familial hypertrophic cardiomyopathy,
dilated cardiomyopathy and thrombotic factors associated with coronary heart disease.
A genetic mutation occurs in the majority of cases of familial hypertrophic cardiomyopathy,
whereas 20% of dilated cardiomyopathy is familial. While coronary heart disease
is usually associated with abnormalities in lipid metabolism, in conjunction with
smoking and or hypertension, a positive family history in the absence of these risk
factors is also associated with the disorder. Thrombotic factors as possible causes
of myocardial infarction are being further investigated. Also, investigations into
the role of the EF-hand calcium-binding protein grancalcin in phagocytes, cells
pivotal in the atherosclerotic process, are being performed.
Research
Focus
Familial hypertrophic cardiomyopathy - a disorder of the
sarcomere?
Hypertrophic cardiomyopathy
is a disorder of myocytes characterised by unexplained cardiac hypertrophy in the
absence of valvular or hypertensive heart disease. It is the major cause of sudden
unexpected cardiac death in young people, and occurs between 0.1 and 1% of the population.
Since 1990 six gene loci encoding sarcomere proteins involved in the contractile
apparatus have been identified: á-myosin heavy changing; troponin T; …-tropomyosin;
myosin binding protein C and essential and regulating myosin light chains. However
these gene loci do not explain all of the familial cases. We had previously clinically
characterised a large cohort of families with hypertrophic cardiomyopathy and current
investigations aim to identify the molecular genetic basis of the disorder in these
pedigrees.
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Familial Dilated Cardiomyopathy
Dilated cardiomyopathy represents a heterogeneous disorder most commonly caused
by coronary heart disease in western countries. However approximately 20% of dilated
cardiomyopathy is familial, and the mode of inheritance in some families is X-linked.
We have identified 2 families in which with characteristic clinical features of
X-linked dilated cardiomyopathy with the disorder occurring in adolescent males
with a progressive clinical deterioration over the following few years to either
death or cardiac transplantation. Dystrophin has been reported as being the candidate
gene in 2 families and we excluded the candidate gene, by sequencing, in one of
the two families identified.
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Molecular genetics and arterial thrombosis. (In collaboration
with the molecular haematology group)
The major causes of coronary heart disease are lipid disorders although the event
precipitating acute coronary syndromes is the development of intra-coronary thrombus.
So far investigations to attempt to identify a role for genetic mutations resulting in a pro-thrombotic tendency in the pathogenesis of acute coronary syndromes, have
been disappointing. We have postulated that this may be because the major risk factor
for coronary heart disease is dyslipidaemia and most patients have extensive atherosclerosis.
We are therefore determining whether Factor V Leiden, a mutation associated with
idiopathic venus thrombosis, is present in increased frequency in young patients
with coronary heart disease who on subsequent arteriography do not have evidence
of severe coronary disease (i.e. there is no coronary stenosis greater than 50%).
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The function of grancalcin and phagocytes
Phagocytes in particular macrophages
play a major role in the pathogenesis of atherosclerosis.
We have identified grancalcin, an EF-hand calcium-binding protein which becomes
granule associated on
cell activation. We are investigating the role of this protein
in phagocyte activation. Such studies will help provide the conceptual basis for
the possible development of future therapies.
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Selected publications
- Boyhan, A., Casimir, C.M., French, J.K., Teahan, C.G., Segal, A.W. (1992). Molecular
cloning and characterization of grancalcin, a novel EF-hand calcium-binding protein
abundant in neutrophils and monocytes. J. Biol. Chem. 267: 2928-33.
- French, J.K.,
Cockcroft, S., Boyhan, A., Teahan, C.G., Segal, A.W. (1993). Grancalcin inhibits
secretion of hexosaminidase in streptolysin-O permeabilised HL60 cells.
Eur. J.
Haematol. 51:330.
- French, J.K. Molecular cardiology: potential for diagnosis and
treatment.
National Heart Foundation of New Zealand, Newmarket, Auckland, New Zealand
Technical Report No. 64. Auckland: October 1994.
- French, J.K., Van de Water, N.S.,
Kaye, S.D., Lander, J., Hyde, T.A., Lund, M., White, H.D., Browett, P.J. (1998).
Factor V Leiden and prothrombin variant G20210A in patients <50 years with recent
acute myocardial infarction and no angiographic stenosis>50%. Circulation (in
press).
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