Malignant hypertrophic cardiomyopathy caused by the Arg723Gly mutation in beta-myosin heavy chain gene.

Mutations causing hypertrophic cardiomyopathy have been described in nine genes encoding sarcomeric proteins. We report a new mutation in three families, with a C-->G transversion in nucleotide 12 307 of the beta-myosin heavy chain gene, located at the essential light chain interacting region, resulting in the replacement of arginine by glycine at amino acid residue 723. PCR amplification of the selected regions followed by single strand conformation polymorphism analysis, DNA sequencing of the polymorphic patterns and restriction analysis were used to detect the mutation. A total of 23 individuals were diagnosed as carriers, and seven were obligate carriers or had been clinically diagnosed. The Arg723Gly mutation was associated with a malignant phenotype. Ten out of 30 affected members died suddenly or needed an implantable cardioverter-defibrillator at a mean age of 42, and seven members developed progressive heart failure, leading to death or heart transplant in five, at a mean age of 50 years. Echocardiography showed non-obstructive left ventricular hypertrophy in affected members older than 20 (sensitivity 68%). Mean survival of affected members was 51 years. In conclusion, a new mutation Arg723Gly in beta-myosin heavy chain gene is reported which shortens life expectancy because of sudden death and end-stage heart failure.

Lack of association between ACE gene polymorphism and left ventricular hypertrophy in essential hypertension.

The possible association between the insertion/deletion (I/D) polymorphism of the angiotensin I converting enzyme (ACE) gene and left ventricular hypertrophy (LVH) was investigated in a group of essential hypertensive patients. Seventy-one essential hypertensive patients (35 men and 36 women), aged 51 +/- 1 years, were genotyped by PCR for the I/D polymorphism of the ACE gene. Cardiac morphology and function were assessed by means of M-mode echocardiography. The relative frequencies of the three genotypes, DD, DI, and II, were respectively: 24%, 55%, and 21%. Mean values of left ventricular mass index were 145, 144, and 150 g/m2 for DD, DI, and II genotypes, without significant differences among them (P = 0.82). Likewise, the prevalence of LVH (76%, 64%, and 87%) was not significantly different among the three genotypes (P = 0.23). We conclude that the ACE gene I/D polymorphism is not associated with LVH in essential hypertension. Journal of Human Hypertension (2000) 14, 47-49.

G-Protein beta(3) subunit gene variant and left ventricular hypertrophy in essential hypertension.

A functional genetic variant consisting of a C825T substitution in the GNB3 gene, encoding for the G-protein beta(3) subunit, has been associated with enhanced G-protein activation and cell growth. The aim of the study was to investigate the association of this polymorphism with left ventricular hypertrophy (LVH) in a sample of patients with essential hypertension. Left ventricular mass was assessed by 2-mode echocardiography in 86 patients with essential hypertension, and GNB3 C825T genotype was determined by polymerase chain reaction and restriction digestion. Thirty-seven (0.43) patients were homozygous for the C allele (CC), 40 (0.47) were heterozygous (CT), and 9 (0.10) were homozygous for the T allele (TT). The genotype distribution among the patients was in Hardy-Weinberg equilibrium. Values of left ventricular end-diastolic diameter (52.0+/-0.7 versus 48.9+/-0.9 mm, P=0.007), posterior wall thickness (11.3+/-0.2 versus 10.6+/-0.2 mm, P=0.042), and left ventricular mass index (152.7+/-4.4 versus 135.2+/-6.4 g/m(2), P=0. 023) were significantly higher in patients with CT and TT genotypes considered together (CT+TT) than in CC patients. The distribution of the genotypes was significantly different when comparing patients with LVH: 20 (0.33) CC and 40 (0.67) CT+TT patients had this complication, and 17 (0.65) CC and 9 (0.35) CT+TT patients did not (P<0.01). The frequency of the T allele was significantly different among patients with (0.40) and without (0.20) LVH (P<0.01). A logistic regression analysis showed that the association between the T allele and LVH was independent of age, mean blood pressure, body mass index, and alcohol consumption. The relative risk of LVH in patients bearing the T allele (CT+TT group) compared with CC hypertensive patients was 3.03 (95% CI 1.14 to 8.05). The findings suggest an association between LVH and the 825T allele in hypertensive patients.

Expression of the Arabidopsis HMG2 gene, encoding 3-hydroxy-3-methylglutaryl coenzyme A reductase, is restricted to meristematic and floral tissues.

The synthesis of mevalonate, which is considered the first rate-limiting step in isoprenoid biosynthesis, is catalyzed by the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR; EC 1.1.1.34). In Arabidopsis, HMGR is encoded by two differentially expressed genes (HMG1 and HMG2). The transcriptional activity of the HMG2 gene was studied after fusing different regions of its 5' flanking region to the beta-glucuronidase (GUS) reporter gene and transforming the resulting constructs into tobacco plants. The spatial and temporal expression directed by the HMG2 promoter in the transgenic plants is consistent with the expression pattern previously established by RNA analysis using an HMG2-specific probe. HMG2 expression is restricted to meristematic (root tip and shoot apex) and floral (secretory zone of the stigma, mature pollen grains, gynoecium vascular tissue, and fertilized ovules) tissues. Deletion analysis of the HMG2 5' flanking region was conducted in transgenic plants and transfected protoplasts. The region containing nucleotides -857 to +64 of the HMG2 gene was sufficient to confer high levels of expression in both floral and meristematic tissues, although deletion to nucleotide -503 resulted in almost complete loss of expression. Sequences contained within the 5' transcribed, untranslated region are also important for gene expression. The biological significance of the restricted pattern of expression of HMG2 is also discussed.

Arabidopsis thaliana contains two differentially expressed 3-hydroxy-3-methylglutaryl-CoA reductase genes, which encode microsomal forms of the enzyme.

The enzyme 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR; EC 1.1.1.34) catalyzes the first rate-limiting step in plant isoprenoid biosynthesis. Arabidopsis thaliana contains two genes, HMG1 and HMG2, that encode HMGR. We have cloned these two genes and analyzed their structure and expression. HMG1 and HMG2 consist of four exons and three small introns that interrupt the coding sequence at equivalent positions. The two genes share sequence similarity in the coding regions but not in the 5'- or 3'-flanking regions. HMG1 mRNA is detected in all tissues, whereas the presence of HMG2 mRNA is restricted to young seedlings, roots, and inflorescences. The similarity between the two encoded proteins (HMGR1 and HMGR2) is restricted to the regions corresponding to the membrane and the catalytic domains. Arabidopsis HMGR2 represents a divergent form of the enzyme that has no counterpart among plant HMGRs characterized so far. By using a coupled in vitro transcription-translation assay, we show that both HMGR1 and HMGR2 are cotranslationally inserted into endoplasmic reticulum-derived microsomal membranes. Our results suggest that the endoplasmic reticulum is the only cell compartment for the targeting of HMGR in Arabidopsis and support the hypothesis that in higher plants the formation of mevalonate occurs solely in the cytosol.