A gene differentially expressed in the kidney of the spontaneously hypertensive rat cosegregates with increased blood pressure.

Samani, Nilesh J.; Lodwick, David; Vincent, Madeleine; Dubay, Christopher; Kaiser, Michael; Kelly, Martin P.; Lo, Ming; Harris, Jennifer A.; Sassard, J; Lathrop, Mark

doi:10.1172/jci116616

Cited by 92 publications

(79 citation statements)

References 28 publications

(37 reference statements)

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“…This pattern of expression was very similar to that of Sa gene transcripts (middle panel). In contrast to the preferential expression of Sa gene transcripts in spontaneously hypertensive rats (13)(14)(15)(16), the levels of MACS1 transcripts were not increased in transcripts in these hypertensive rats (data not shown). We also analyzed dietary regulation of MACS1 and Sa mRNAs in the liver by Northern blotting.…”

Section: Comparison Of Amino Acid Sequences Of Macs1 and Samentioning

confidence: 71%

“…The Sa gene has been characterized as a proposed candidate gene for essential hypertension (13)(14)(15)(16)(17)(18)(19). Although congenic substitution mapping argued for the Sa gene locus as a candidate for the blood pressure quantitative trait locus (20), the function of the Sa gene product was unclear until now.…”

Section: Fig 3 Substrate Specificities and Kinetic Properties Of Pumentioning

confidence: 99%

“…The Sa gene is highly expressed in the hypertensive kidney (11,12) and its increased expression correlates with increased blood pressure in both spontaneously hypertensive (13)(14)(15)(16) and Dahl hypertensive (17)(18)(19) rat models. However, although recent congenic substitution mapping studies have argued that the Sa gene is a candidate gene locus for hypertension (20), the function of the Sa gene remains unclarified.…”

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confidence: 99%

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Molecular Identification and Characterization of Two Medium-chain Acyl-CoA Synthetases, MACS1 and the Sa Gene Product

Fujino¹,

Takei²,

Sone³

et al. 2001

Journal of Biological Chemistry

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In this study, we identified and characterized two murine cDNAs encoding medium-chain acyl-CoA synthetase (MACS). One, designated MACS1, is a novel protein and the other the product of the Sa gene (Sa protein), which is preferentially expressed in spontaneously hypertensive rats. Based on the murine MACS1 sequence, we also identified the location and organization of the human MACS1 gene, showing that the human MACS1 and Sa genes are located in the opposite transcriptional direction within a 150-kilobase region on chromosome 16p13.1. Murine MACS1 and Sa protein were overexpressed in COS cells, purified to homogeneity, and characterized. Among C4 -C16 fatty acids, MACS1 preferentially utilizes octanoate, whereas isobutyrate is the most preferred fatty acid among C2-C6 fatty acids for Sa protein. Like Sa gene transcript, MACS1 mRNA was detected mainly in the liver and kidney. Subcellular fractionation revealed that both MACS1 and Sa protein are localized in the mitochondrial matrix. 14 C-Fatty acid incorporation studies indicated that acyl-CoAs produced by MACS1 and Sa protein are utilized mainly for oxidation.

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Section: Comparison Of Amino Acid Sequences Of Macs1 and Samentioning

confidence: 71%

Section: Fig 3 Substrate Specificities and Kinetic Properties Of Pumentioning

confidence: 99%

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confidence: 99%

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Molecular Identification and Characterization of Two Medium-chain Acyl-CoA Synthetases, MACS1 and the Sa Gene Product

Fujino¹,

Takei²,

Sone³

et al. 2001

Journal of Biological Chemistry

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“…Such a conclusion is of course crucially dependent on the reliability of the BP assessment. We used a very standard method for short-term direct BP measurement in conscious unrestrained rats, similar to one that we have previously used in other hypertension co-segregation studies [27]. Furthermore, the same technique easily showed a difference in SBP and DBP between the two progenitor strains and in the F 2 rats the full range of readings between hHTg and BN rats was observed.…”

Section: Discussionmentioning

confidence: 98%

Mapping of genetic loci predisposing to hypertriglyceridaemia in the hereditary hypertriglyceridaemic rat: analysis of genetic association with related traits of the insulin resistance syndrome

et al. 2003

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Aims/hypothesis. Hypertriglyceridaemia is an important risk factor for coronary heart disease, especially in the context of the insulin resistance syndrome where it often occurs with hypertension. The two phenotypes are also associated in the hereditary hypertriglyceridaemic (hHTg) rat. The aim of this study was to map quantitative trait loci that affect plasma triglyceride concentration in the hHTg rat and determine whether they co-localize with loci for blood pressure. Methods. Second filial generation progeny (n=189) from a cross of the hHTg rat with the Brown Norway rat were phenotyped for fasting plasma triglyceride, glucose and insulin concentrations, and direct unrestrained resting blood pressure. A partial genome-scan was conducted using 153 microsatellite markers that were polymorphic between the two strains. Results. A major locus (lod score 6.5) influencing plasma triglyceride concentration in a co-dominant fashion was mapped to chromosome 4 between D1Mit5 and D1Mit17. Chromosome 8 contained multiple peaks with a lod score greater than 4.0 influencing triglyceride concentration. Importantly, none of the triglyceride loci had an effect on blood pressure. The triglyceride locus on chromosome 4 co-localized with a locus for fasting plasma insulin (lod score 4.1), although the effect on insulin concentration was in the opposite direction to that on triglyceride. Conclusion/interpretation. We have mapped the major loci that affect plasma triglyceride concentration in the hHTg rat. These loci do not influence blood pressure suggesting that these commonly associated phenotypes of the insulin resistance syndrome are not be due to pleiotropic effects of the same gene(s). [Diabetologia (2003) 46:352-358]

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“…It was first found to be differentially expressed in the kidneys, a prominent candidate organ for BP regulation, in comparisons between Wistar-Kyoto and spontaneously hypertensive rat strains. More promising was the fact that it was found later to co-segregate with BP in linkage analyses (Iwai et al, 1992;Samani et al, 1993). However, subsequent physical mapping has ruled it out: the SA gene was contained in congenic intervals, yet the congenic strains failed to show any BP effect (Hubner et al, 1999;St Lezin et al, 2000).…”

Section: Use Of Heterozygotes As a Deductive Functional Test Of Qtlsmentioning

confidence: 99%

Individual QTLs controlling quantitative variation in blood pressure inherited in a Mendelian mode

Duong

Charron

Deng³

et al. 2006

Heredity

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We studied three possible genotypes at 10 well-defined blood pressure (BP) QTLs using congenic rat lines. The central question was whether the hypertensive or normotensive allele is dominant, or whether there is partial dominance. The congenic strains were employed to investigate the BP effects of alleles originating from normotensive rats in the background of hypertensive Dahl salt-sensitive (DSS) rats. The normotensive alleles at eight QTLs were fully dominant over DSS alleles, which we tentatively interpreted as indicating that DSS rats incurred a loss of function at these loci and that the QTLs produced BP-reducing agents. In contrast, the normotensive allele of only one QTL was recessive over its DSS counterpart, implying a gain of function at this QTL or a null allele involved in generating a BP-elevating agent. Only one locus, C17QTL, had alleles exhibiting partial dominance. These estimates of dominance differ considerably from those obtained by QTL analysis in a F2 cross. This disagreement demonstrates the importance of establishing a cause-effect relationship between a QTL and its phenotypic effect via congenic strains. The dominance relationships suggest pertinent strategies for gene identification and pharmaceutical intervention.

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A gene differentially expressed in the kidney of the spontaneously hypertensive rat cosegregates with increased blood pressure.

Cited by 92 publications

References 28 publications

Molecular Identification and Characterization of Two Medium-chain Acyl-CoA Synthetases, MACS1 and the Sa Gene Product

Molecular Identification and Characterization of Two Medium-chain Acyl-CoA Synthetases, MACS1 and the Sa Gene Product

Mapping of genetic loci predisposing to hypertriglyceridaemia in the hereditary hypertriglyceridaemic rat: analysis of genetic association with related traits of the insulin resistance syndrome

Individual QTLs controlling quantitative variation in blood pressure inherited in a Mendelian mode

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