Molecular basis of familial cardiomyopathies.
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Amino Acids↗
Biomedical subjects
P Guicheney
Publications and source records attributed to P Guicheney.
[Hypertrophic cardiomyopathy: practical application of genetic research].
Hypertrophic cardiomyopathy is usually familial with an autosomal dominant mode of transmission. The condition is genetically heterogeneous. The first defective gene to be described was that of the beta heavy chain of cardiac myosin (beta-MHC, chromosome 14 q11-q12) where over 20 different localised false sense mutations and a hot point of mutation in exon 13 have been reported. This locus seems to be implicated in 30% of families studied. Systematic screening of the genome has led to the detection of new sites on chromosomes 1, 11 and 15. No gene has yet been identified in these three new loci. For all new families, present strategy consists in determining the locus responsible for the disease by linkage analysis. For beta-MHC locus a panel of several markers (the two MYO I and MYO II microsatellites of the beta-MHC gene and two new AFN microsatellites) has been established which allows accurate detection of whether the haplotype cosegregates with the disease, even in relatively small families. It is then necessary to define the mutation by PCR amplification of the exons followed by electrophoresis on Hydrolink-MDE gels and sequencing of the mutant exons. Some subjects are genotypically affected but phenotypically normal and it seems the penetrance varies with the type of mutation. Analysis of the genotype/phenotype relationship should be continued in order to improve our knowledge of the consequences of each mutation. The genotype diagnosis is therefore complex and cannot be undertaken at present of the examination of the propositus. Whole families must be sampled.(ABSTRACT TRUNCATED AT 250 WORDS)
Cardiomyopathy, Hypertrophic↗
Readjusting the localization of long QT syndrome gene on chromosome 11p15.
Long QT syndrome (LQT) is an autosomal dominant cardiac disease characterized by ventricular arrhythmia. A first locus for LQT has been identified on chromosome 11p15.5 (LQT1), closely linked to HRAS. To refine the location of LQT1, microsatellites were genotyped in 8 French families and the following order was determined: tel-HRAS-DRD4-D11S922-D11S4046- IGF2-INS-TH-D11S1318-D11S1323-D11S1338-D11S90 9-D11S1346-cen. By haplotype analysis, 12 crossing-over events were identified in affected and unaffected subjects, delineating the LQT1 candidate region to 7 cM. This new delineated localization between D11S1318 and D11S1323 is in a more centromeric region than previously thought and is 5 cM proximal to HRAS.
Chromosome Mapping↗
Identification of a mutation near a functional site of the beta cardiac myosin heavy chain gene in a family with hypertrophic cardiomyopathy.
Several mutations within the gene coding for the cardiac beta myosin heavy chain (designed MYH7) have been shown to be responsible for Familial Hypertrophic Cardiomyopathy (FHC) in several families, and evidence of genetic heterogeneity has been reported. To investigate the MYH7 gene as the cause of the disease in a small family with FHC, inheritance of the disease and chromosome 14 q11-q12 markers haplotype were studied, exons coding for the head domain of the cardiac beta myosin heavy chain (beta MHC) were analysed for mutations by MDE gel electrophoresis, and sequenced. We report a mutation within exon eight of the MYH7 gene at a very conserved amino acid at position 232, which results in the conversion of an asparagine to serine. This residue Asn-232 is located in a MHC area that has been recently identified as a critical site for ATPase activity. According to recent results on the three-dimensional structure of the myosin head or subfragment-1 (S1), Asn-232 is located in an alpha-helix which forms part of the nucleotide binding pocket. Although this mutation affects an active site, it seems to be associated with a favourable prognosis and a weak penetrance in this family.
Adult↗
Localization of merosin-negative congenital muscular dystrophy to chromosome 6q2 by homozygosity mapping.
Congenital muscular dystrophies (CMD) are autosomal recessive, heterogeneous disorders. The commonest forms are the Fukuyama CMD (FCMD), associated with mental retardation and structural brain anomalies, and classical (occidental) CMD, with pure muscle expression. FCMD has been localized to chromosome 9q31-q33. Following the discovery of merosin deficiency in some CMD cases, we have localized, by homozygosity mapping and linkage analysis (Zmax = 5.6; theta = 0.0 for marker AFM127xb2) in four merosin-negative families a CMD gene in a 16 cM region of chromosome 6q2 in the region of the laminin M chain gene. In three consanguineous, merosin-positive, CMD families there was no linkage to either chromosome 6q2 or 9q31-q33.
Chromosome Mapping↗
[Physiopathology of mitral mechanics in hypertrophic cardiomyopathy. Groupe de travail "Cardiomyopathies et insuffisance cardiaque" de la Société Française de Cardiologie].
Ventricular hypertrophy, the only indisputable phenotypical marker of hypertrophic cardiomyopathy, is the basis of the physiopathology and treatment of the disease. Mitral valve abnormalities are usually considered to be secondary to the hypertrophy but the genesis of systolic anterior motion by the Venturi effect has been questioned by many clinical and experimental observations. Abnormalities of the mitral valve apparatus may in themselves (elongation of the valves, antero-internal malposition of the mitral papillary muscles and/or hyperlaxicity of antero-internal corhdae tendinae) create systolic anterior motion or subaortic obstruction in the absence of septal hypertrophy and/or increased subaortic flow velocities. Anatomo-clinical studies have confirmed this hypothesis: a high prevalence of mitral valve disease (increased valvular surface and length) has been found in hypertrophic cardiomyopathy. The recognition of these abnormalities is of value from the therapeutic (mitral valvuloplasty) diagnostic (in borderline cases) and genetic (when the primary nature of the abnormalities is confirmed) points of view.
Animals↗
Dissociation of hypertension and genetically enhanced cell growth capacity in skin fibroblasts of F2 hybrid spontaneously hypertensive rats/Wistar-Kyoto rats.
Skin fibroblasts from newborn spontaneously hypertensive rats (SHR) grow faster in culture than Wistar-Kyoto rat (WKY) cells. Similar results have been described for vascular smooth muscle cells from prehypertensive and adult SHR. This suggests the existence of an intrinsic abnormality in vascular and nonvascular cells of mesodermal origin affecting cell growth control in those rats. In an attempt to determine the relation between high blood pressure and this trait, we cultured skin fibroblasts from adult SHR, WKY, F1, and F2 hybrid SHR/WKY populations by explant technique. Their growth capacity was determined by culture well DNA doubling time and by [3H]thymidine incorporation. Adult SHR fibroblasts grew more quickly (doubling time [DT] = 37.2 +/- 2.3 h, n = 8) than WKY ones (DT = 53.9 +/- 3.6 h, n = 6). Female SHR were crossed with male WKY to produce an F1 and an F2 hybrid generation presenting a Mendelian distribution of blood pressure. Skin fibroblasts were cultured from 21 rats belonging to the highest and the lowest blood pressure groups. No difference was observed between the two groups in either growth (DT = 47.5 +/- 4.1 h, n = 11 v DT = 44.6 +/- 3.2 h, n = 10) or epidermal growth factor-induced [3H]thymidine incorporation. These observations suggest that the increased growth capacity observed in SHR is not a determinant of high blood pressure initiation but may be involved in early cardiovascular enlargement.
Animals↗
High cardiac zinc levels in spontaneously hypertensive rats.
OBJECTIVES: Higher cardiac zinc levels have been observed previously in spontaneously hypertensive rats (SHR) compared with Wistar-Kyoto (WKY) rats. However, this difference was established in adult males only and needed to be confirmed on a larger number of animals of both sexes. We also explored the respective roles of genetic and environmental factors in the genesis of this zinc anomaly as well as the causal relations with hypertension. DESIGN: Cardiac zinc levels were determined in adult male and female SHR and WKY rats originating from various colonies and submitted to various experimental conditions (anaesthesia, stress). These determinations were also performed in 3-week prehypertensive SHR and in adult Wistar rats submitted or not to deoxycorticosterone acetate-salt-induced hypertension. METHOD: Zinc levels were measured by flame atomic absorption spectrophotometry. RESULTS: In adults, cardiac zinc content was significantly higher in SHR than in WKY rats irrespective of sex and experimental conditions. In young prehypertensive rats, the difference between SHR and WKY cardiac zinc levels was also very significant. Experimental hypertension induced in Wistar rats did not entail any significant rise in cardiac zinc levels. CONCLUSIONS: These findings indicated that the higher cardiac zinc of SHR is not secondary to blood pressure elevation. High erythrocyte zinc, previously described in SHR, together with the present data suggest the occurrence of a primary genetic defect leading to high intracellular zinc in SHR. The possible role of this zinc anomaly in the development of hypertension and/or cardiac hyperplasia is discussed.
Aging↗
Predisposition to essential hypertension and renal hemodynamics in recent-onset insulin-dependent diabetic patients.
The offspring of essential hypertensive parents have been found to exhibit abnormalities in renal hemodynamics and sodium handling before the eventual occurrence of hypertension. The reported abnormalities represent a wide spectrum of changes including increased GFR, normal or decreased RPF, slight increase in blood pressure (although within the normal range), and an exaggerated natriuresis response to a sodium load. The heterogeneity of these abnormalities may reflect the specific conditions of the studies, the lability of the changes, or different subgroups of subjects with genetic predisposition to essential hypertension. Several lines of evidence have suggested a relationship between hypertension and the development of diabetic nephropathy in insulin-dependent diabetics. This laboratory has found that recent-onset insulin-dependent diabetics can exhibit renal hemodynamics abnormalities very early in the course of diabetes according to a positive or negative family history of essential hypertension. These changes include increased GFR and mean arterial pressure, but no differences in renal sodium and lithium handling in diabetics with a genetic predisposition to essential hypertension. In addition, diabetics with a positive family history of essential hypertension exhibited a more-marked vasodilative response to an acute interruption of the renin-angiotensin system, further suggesting inadequate angiotensin modulation of renal vascular tone. The significance of these abnormalities in relation to the development of diabetic nephropathy requires further investigation.
Angiotensin-Converting Enzyme Inhibitors↗
Na(+)-H+ exchange activity in skin fibroblasts from hyperfiltering insulin-dependent diabetics.
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Adult↗
Dissociation between derepressed K+,Cl- cotransport system and high blood pressure in the F2 hybrid generation (SHR x WKY).
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Animals↗
Enhanced response to growth factors and to angiotensin II of spontaneously hypertensive rat skin fibroblasts in culture.
Skin fibroblasts from newborn spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats were cultured to study their growth rate and their reactivity to various agonists in terms of mitogenic potency and inositol phosphate production. A marked enhancement of nuclear 3H-thymidine incorporation, occurring after stimulation of quiescent fibroblasts by fetal calf serum, correlated with the increased growth rate of these cells with regard to WKY ones. Insulin (1 microgram/ml) and epidermal growth factor (10 ng/ml) induced two and four times greater DNA synthesis in SHR fibroblasts compared to WKY cells, without activating the phospholipase C pathway. In contrast, angiotensin II, bradykinin, vasopressin which stimulated inositol phosphate production, and phorbol-12 myristate 13-acetate were unable to stimulate DNA synthesis. Higher levels of tritiated inositol phosphates were produced in SHR cells after serum, bradykinin and angiotensin II stimulation, but not in WKY cells after vasopressin. This enhanced mitogenic response of SHR skin fibroblasts is probably due to a genomic alteration and appears to be independent of the hyperactivation of the phospholipase C to some vasoactive agonists.
Angiotensin II↗
Enhanced cell proliferation in essential hypertension.
In order to define the molecular mechanism involved in enhancement of spontaneously hypertensive rat (SHR) cell proliferation, we have compared the actions of fetal calf serum (FCS) and angiotensin II on both SHR and Wistar-Kyoto (WKY) rat aortic smooth muscle cells. Both compounds are more mitogenic in SHR cells than in controls. However, phospholipase C (PLC) hyperresponsiveness can be seen only under angiotensin stimulation, as are the expressions of c-jun, c-fos, and c-myc. Oncogene overexpression therefore appears to be more strongly related to PLC hyperreactivity than to enhanced proliferation of SHR aortic smooth muscle cells.
Angiotensin II↗
[Genetic abnormalities in cultured cutaneous fibroblasts in SHR rats].
Skin fibroblasts were isolated from newborn spontaneously hypertensive rats (SHR) and Wistar-Kyoto normotensive rats (WKY) to study their cell growth and reactivity in culture. SHR fibroblasts exhibited an enhanced growth rate in presence of 10 per cent fetal calf serum and a marked increase in 3H thymidine incorporation compared to WKY cells, when confluent quiescent fibroblasts were stimulated by 2, 5, 10 or 15 per cent serum as well as by 10 ng/ml EGF. Inositol phosphate formation determined by exchange chromatography in presence of 20 mM LiC1, was stimulated by serum, 1 microM angiotensin II, I microM bradykinin and 0.1 microM vasopressin in both type of cells labelled with 3H myoinositol. Significantly higher levels were produced in SHR cells by angiotensin II, serum and bradykinin compared to WKY fibroblasts. No difference between the two cell groups was observed with vasopressin. The intracellular pH (pHi) of isolated SHR and WKY fibroblasts was measured in bicarbonate-free medium using the fluorescent dye BCECF. The identical pHi values (7.03 +/- 0.10, n = 5 and 7.04 +/- 0.07, n = 6 for WKY and SHR respectively agree with an absence of Na+/H+ antiport activation in unstimulated cells. This study allows to conclude that skin fibroblasts isolated from newborn SHR, similarly to vascular smooth muscle cells, exhibit an hyperresponsiveness to serum, EGF and angiotensin II. These results demonstrate the presence of an intrinsic cellular developing capacity.
Animals↗
Free and conjugated plasma homovanillic acid in schizophrenic patients.
It has recently been suggested that the plasma level of homovanillic acid (HVA) may provide an index of central dopaminergic activity in humans. Clinical studies have shown that in schizophrenic patients, plasma HVA levels increase with the severity of psychopathology. However, these studies only considered the plasma free HVA fraction whereas investigations on conjugated HVA in humans are sparse and results remain controversial. The aim of this study was to measure both plasma free and conjugated HVA in healthy volunteers and drug-free schizophrenic patients. The mean values and the ranges of plasma free HVA in volunteers and patients were similar to those described in the literature. A substantial and significant increase in plasma free HVA was observed in schizophrenic patients compared with normal subjects. In contrast, plasma conjugated HVA was significatively decreased in schizophrenics. The plasma total HVA was nevertheless higher in schizophrenics compared with controls. No significant correlations were observed between plasma HVA levels and the clinical features of schizophrenic patients rated by various psychiatric scales. These findings suggest that there is an imbalance between plasma free and conjugated HVA in schizophrenic patients, who present an increase in total HVA when compared with controls. Paranoid schizophrenic patients, who present mainly positive symptoms, show the most marked plasma free/conjugated HVA imbalance.
Adolescent↗
Increased response to growth factors of skin fibroblasts from newborn spontaneously hypertensive rats.
Skin fibroblasts were isolated from newborn spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) and cultured with 10% fetal calf serum. The growth rate, determined by the culture dish DNA content, was significantly higher in cells from SHR than from WKY in the presence of 10 and 15% serum. Re-initiation of DNA synthesis by serum and insulin was assessed by 24-h 3H-thymidine incorporation in quiescent cells. Serum (5, 10 and 15%) and insulin (1 microgram/ml) induced a marked stimulation of 3H-thymidine incorporation, and the cell response was significantly higher in SHR than in WKY for both agonists. These results indicate that the hyper-responsiveness to growth factors evident in newborn SHR skin fibroblasts is a genetic defect independent of haemodynamic changes.
Animals↗
Phenylephrine, vasopressin and angiotensin II as determinants of proto-oncogene and heat-shock protein gene expression in adult rat heart and aorta.
The expression of two oncogenes (conc) c-myc and c-fos, coding for nuclear proteins which play a regulatory role in growth and differentiation, and of two genes coding for two heat shock proteins (HSP) 68 (molecular weight 68,000) and 70 (molecular weight 70,000), which have a protective function during stress, have been investigated by Northern blot analysis of the total RNA, extracted from adult rat ventricle and aorta. (1) The two onc transcripts are absent from these tissues but their expression can be enhanced by a pretreatment with cycloheximide. (2) The HSP70 is, in part, constitutive, while HSP68 is not; both are thermo-inducible in an isolated coronary perfused rat heart. (3) The four messenger RNA (mRNA) are expressed in both ventricles and aorta, 1 or 2 hours after i.p. injection of 6 mg/kg phenylephrine or 12 IU/kg of vasopressin. (4) They are also induced by a continuous or discontinuous injection of angiotensin II (7.5 micrograms/kg per min) for 1-2 h, but only in the aorta. The lack of ventricular response to angiotensin II in rat ventricles has been attributed to the lack of angiotensin II receptors in this tissue. This indicates that, in addition to mechanical factors, circulating hormones which have in common the use of the phosphoinositol pathway, may activate the expression of genes coding for regulatory proteins. This may play a role in the genesis of both ventricular and aortic hypertrophy.
Angiotensin II↗
Platelet 5-HT content and uptake in essential hypertension: role of endogenous digitalis-like factors and plasma cholesterol.
A decrease in platelet 5-HT content linked to partial inhibition of 5-HT uptake has been described in essential hypertension. Transport of 5-HT through platelet membrane is dependent upon transmembranal Na+ and K+ gradients. It is inhibited by Na+, K+-ATPase inhibitors such as ouabain and endogenous digitalis-like compounds isolated from hemodiafiltrate. The activity of such compounds in plasma extracts, measured by inhibition of Na+,K+-ATPase or ouabain binding to human erythrocytes, and platelet 5-HT content were determined in parallel in essential hypertensive patients. Significant negative correlations were observed between these parameters in men, suggesting that high levels of digitalis-like compounds can affect platelet 5-HT content. In addition, in essential hypertensive patients, total plasma cholesterol was inversely related to both platelet 5-HT content (n = 15, r = -0.594, P less than 0.02) and maximal velocity of 5-HT uptake (n = 15, r = -0.717, P less than 0.003). In normotensive control subjects, no variation of platelet 5-HT content with cholesterol was observed. This suggests that the platelet membranes of essential hypertensive patients are more sensitive to increases in plasma cholesterol than those of normotensive subjects.
Adult↗