Organic aciduria and butyryl CoA dehydrogenase deficiency in BALB/cByJ mice

Schiffer, Stephen P.; Procházka, Michal; Jezyk, Peter F.; Roderick, Thomas H.; Yudkoff, Marc; Patterson, Donald F.

doi:10.1007/bf00563017

Cited by 20 publications

(15 citation statements)

References 19 publications

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“…Surprisingly, Acads Ϫ/Ϫ mice have no apparent clinical disease (3). More subtle phenotypes include organic aciduria (38,51), fatty liver and kidney (3), cold intolerance (16), fasting-induced hypoglycemia (51), and slowing of theta oscillations during sleep (49). SCAD deficiency also occurs in humans and in its most severe form is characterized by metabolic acidosis, nonketotic hypoglycemia, and short-chain dicarboxylic aciduria (51).…”

Section: Discussionmentioning

confidence: 99%

“…The BALB/cByJ mice selected a lower percentage of fat intake (36%) than all other strains tested with the exception of the CAST/Ei (25%) (43). The BALB/cByJ mouse strain bears a spontaneous deletion in the short-chain acyl-CoA dehydrogenase (SCAD) structural gene (Acads) (38,51) that results in missplicing of the mRNA and the absence of functional SCAD (18; for review, see Refs. 38 and 52).…”

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Mice bearing Acads mutation display altered postingestive but not 5-s orosensory response to dietary fat

Richards¹,

Belton²,

York³

et al. 2004

American Journal of Physiology-Regulatory, Integrative and Comp

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. Mice bearing Acads mutation display altered postingestive but not 5-s orosensory response to dietary fat. Am J Physiol Regul Integr Comp Physiol 286: R311-R319, 2004. First published October 30, 2003 10.1152/ajpregu.00488.2003.-A previous survey of mouse inbred strains revealed a wide range in selfselected fat intake, from 26 to 83% of energy. The BALB/cByJ strain selected a lower percentage of fat intake (36%) than all other strains tested except for the CAST/Ei. BALB/cByJ mice are deficient in the short-chain acyl-CoA dehydrogenase (SCAD) enzyme due to a spontaneous mutation in Acads. We hypothesized that this deficiency would alter fat appetite and used three behavioral test paradigms to compare the response of BALB/cByKz.Acads Ϫ/Ϫ and BALB/ cByKz.Acads ϩ/ϩ mice to fat stimuli. First, during 10-day exposure to a macronutrient self-selection diet, Acads Ϫ/Ϫ mice consumed proportionately less fat and more carbohydrate than Acads ϩ/ϩ mice, yet total energy intake was similar between strains. Next, in 48-h two-bottle preference tests, Acads ϩ/ϩ mice displayed a preference for 50% corn oil, but Acads Ϫ/Ϫ mice did not. Finally, in brief-access taste tests employing successive 5-s presentations of corn oil in an ascending concentration series ending with 50%, there were no effects of strain on total licks, indicating that Acads does not alter acute orosensory response to this fat stimulus. With 15-s presentations, however, the Acads ϩ/ϩ mice licked more of the 50% oil than Acads Ϫ/Ϫ, suggesting orosensory effects related to the increased exposure time. In contrast to corn oil, there were no strain differences in licking response to sucrose solution in either the two-bottle or brief-access taste tests. The observation that SCAD-deficient mice display altered postingestive responses to dietary fat provides further evidence for the metabolic control of feeding. taste; ingestive behavior; licking frequency; diet selection IN A PHENOTYPIC SURVEY of mouse inbred strains, self-selected fat consumption ranged from 26 to 83% of total energy across strains in a choice paradigm containing separate sources of carbohydrate, fat, and protein (43). The BALB/cByJ mice selected a lower percentage of fat intake (36%) than all other strains tested with the exception of the CAST/Ei (25%) (43). The BALB/cByJ mouse strain bears a spontaneous deletion in the short-chain acyl-CoA dehydrogenase (SCAD) structural gene (Acads) (38, 51) that results in missplicing of the mRNA and the absence of functional SCAD (18; for review, see Refs. 38 and 52). SCAD is a mitochondrial enzyme that catalyzes the first reaction in the ␤-oxidation of C 4 -C 6 fatty acids. We hypothesized that this deficiency in ␤-oxidation of fatty acids may underlie the observed dietary preference.Fatty acid oxidation is thought to be a key factor in the metabolic control of food intake (10) because rodents are stimulated to eat after administration of inhibitors that interfere with ␤-oxidation of fatty acids (36-37). For example, administration of mercaptoacetate (MA) st...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Mice bearing Acads mutation display altered postingestive but not 5-s orosensory response to dietary fat

Richards¹,

Belton²,

York³

et al. 2004

American Journal of Physiology-Regulatory, Integrative and Comp

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“…An Acads deletion appeared spontaneously in the 3 ′ end of the gene in BALB/cBy after the separation of this strain from BALB/c, causing a defi ciency in ACADS activity in BALB/cBy that is not present in BALB/c ( 18 ). We examined ACADS protein levels in livers from BALB/cBy and BALB/c mice by Western blotting analysis and verifi ed that ACADS was totally defi cient in BALB/cBy mice ( Fig.…”

Section: Balb/cby Mice Which Are Defi Cient In Acads Have Higher Hdmentioning

confidence: 97%

“…Acads encodes short-chain acylCoA dehydrogenase, which participates in the ␤ -oxidation of short-chain fatty acids. Acads -defi cient BALB/cByJ mice accumulate and secrete fatty acid metabolites in the urine and develop fatty liver with hypoglycemia after fasting for 18 h ( 18,19 ). Unsaturated fatty acids destabilize ABCA1, increase its degradation, and inhibit cholesterol effl ux from macrophages ( 20,21 ).…”

Section: Downloaded Frommentioning

confidence: 99%

Untangling HDL quantitative trait loci on mouse chromosome 5 and identifying Scarb1 and Acads as the underlying genes

Leduc

Korstanje

et al. 2010

Journal of Lipid Research

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This article is available online at http://www.jlr.org human populations; these QTL often map to homologous locations in both species ( 1 ). Detecting QTL has been relatively easy. The next step of identifying causal QTL genes, however, has been more challenging, although the development of bioinformatic methods ( 2, 3 ) and improved genomic resources in the mouse ( 4 ) and genomewide association studies in humans ( 5, 6 ) are improving the success of QTL gene identifi cation.QTL that are in close proximity on the same chromosome remain particularly challenging. In such situations, it is particularly diffi cult to identify the causal QTL genes. Although congenic strains are a powerful tool to separate these QTL, they are time consuming; therefore, we used a more effi cient, genomic approach to decipher the presence of one or multiple QTL and identify the QTL genes. At least seven inbred mouse crosses ( 7-12 ) have identifi ed HDL QTL on mouse distal chromosome (Chr) 5 ( Table 1 ). However, the broad confi dence intervals and shape of the logarithm of the odds ratio (LOD) score plots suggest that at least four of these crosses (B6 × 129, NZB × SM, B6 × NZB, and B6 × CAST) may have two closely linked QTL. We used advanced intercross lines between B6 and NZB at F11, which allows the accumulation of recombination events and thus narrows QTL ( 13 ) and confi rmed that two QTL did exist between these two strains on distal Chr 5. These QTL were named Hdlq1 at 125 Mb and Hdlq8 at 113 Mb ( 11 ).In the present study, we fi rst identifi ed Scarb1 as the causal gene for Hdlq1 . We then confi rmed that Hdlq8 is an independent QTL by crossing two closely related strains that do not differ at the Scarb1 locus and thus were expected not to have a QTL at the Hdlq1 region. As expected, this cross detected Hdlq8 but had no QTL at Hdlq1. Subsequently, we used haplotype analysis, gene sequencing, expression studies, and a spontaneous mutation to demonstrate that Acads was the underlying gene for Hdlq8 .Abstract Two high-density lipoprotein cholesterol quantitative trait loci (QTL), Hdlq1 at 125 Mb and Hdlq8 at 113 Mb, were previously identifi ed on mouse distal chromosome 5. Our objective was to identify the underlying genes. We fi rst used bioinformatics to narrow the Hdlq1 locus to 56 genes. The most likely candidate, Scarb1 (scavenger receptor B1), was supported by gene expression data consistent with knockout and transgenic mouse models. Then we confi rmed Hdlq8 as an independent QTL by detecting it in an intercross between NZB and NZW (LOD = 12.7), two mouse strains that have identical genotypes for Scarb1 . Haplotyping narrowed this QTL to 9 genes; the most likely candidate was Acads (acyl-coenzymeA dehydrogenase, short chain). Sequencing showed that Acads had an amino acid polymorphism, Gly94Asp, in a conserved region; Western blotting showed that protein levels were signifi cantly different between parental strains. A previously known spontaneous deletion causes loss of ACADS activity in BALB/cBy mice. We showed that HDL le...

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“…Some of the mouse genes around this region have already been mapped, and each human counterpart was localized to 12q23-24. [46][47][48] The human chromosome 12q23-24 is one of the best-characterized regions of the human genome. Several genes mapped on this region are involved in inherited diseases, including many kinds of metabolic diseases (Fig.…”

Section: Discussionmentioning

confidence: 99%

Mouse Homologue of the Human SART3 Gene Encoding Tumor‐rejection Antigen

Harada

Yamada

Mizutani

et al. 2000

Japanese Journal of Cancer Research

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We recently isolated a human SART3 (hSART3) gene encoding a tumor-rejection antigen recognized by HLA-A2402-restricted cytotoxic T lymphocytes (CTLs). The hSART3 was also found to exist as an RNA-binding nuclear protein of unknown biological function. In this study, we cloned and analyzed the homologous mouse SART3 (mSART3) gene in order to understand better the function of hSART3, and to aid in establishing animal models of specific immunotherapy. The cloned 3586-bp cDNA encoded a 962-amino acid polypeptide with high homology to hSART3 (80% or 86% identity at the nucleotide or protein level, respectively). Nonapeptides recognized by the HLA-A2402-restricted CTLs and all of the RNA-binding motifs were conserved between hSART3 and mSART3. The mSART3 mRNA was ubiquitously expressed in normal tissues, with low level expression in the liver, heart, and skeletal muscle. It was widely expressed in various organs from as early as day 7 of gestation. mSART3 was mapped to chromosome 5, a syntenic region for human chromosome 12q23-24, and its genomic DNA extended over 28-kb and consisted of 19 exons. This information should be important for studies of the biological functions of the SART3 protein and for the establishment of animal models of specific cancer immunotherapy.Key words: SART3 -Tumor-rejection antigen -RNA-binding protein -HLA-A2402 -Cytotoxic T lymphocytesOne of the most significant advances in the field of tumor immunology has been the recent identification of genes encoding tumor-rejection antigens that are recognized by HLA-class-I-restricted and tumor-specific cytotoxic T lymphocytes (CTLs).1, 2) The potential application of these findings to the development of cancer vaccines has brought nearer the prospect of specific cancer immunotherapy. Indeed, several peptides encoded by these genes are now under clinical trial as cancer vaccines, and major tumor regression has been observed in some melanoma patients.3, 4) We have recently isolated a human SART3 (hSART3) gene encoding a tumor-rejection antigen from cDNA of a human esophageal cancer cell line. 5) Two SART3-derived peptides, at positions 109-118 and 315-323, that are recognized by HLA-A2402-restricted CTLs, are able to induce HLA-A2402-restricted and tumorspecific CTLs from peripheral blood mononuclear cells (PBMCs) of HLA-A24 positive (HLA-A24 + ) cancer patients. hSART3 encodes a Mr 140 000 protein expressed in both the cytosol of the majority of proliferating cells, including non-tumorous cell lines, and the nucleus of the majority of cancer cells. However, the SART3 protein was undetectable in normal tissues except for the testis and fetal liver, regardless of its ubiquitous expression at the mRNA level.5) There are several motifs in the sequence of the SART3 protein: nuclear localization signals 6) around positions 612-615 and 641-647, a ribonucleoprotein-1 (RNP-1) motif, 7) one of the well-characterized RNA-binding motifs, at positions 746-753 and 841-848, and a tyrosine phosphorylation motif 8) at positions 309-316. The involvement of the SART3 ...

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Organic aciduria and butyryl CoA dehydrogenase deficiency in BALB/cByJ mice

Cited by 20 publications

References 19 publications

Mice bearing Acads mutation display altered postingestive but not 5-s orosensory response to dietary fat

Mice bearing Acads mutation display altered postingestive but not 5-s orosensory response to dietary fat

Untangling HDL quantitative trait loci on mouse chromosome 5 and identifying Scarb1 and Acads as the underlying genes

Mouse Homologue of the Human SART3 Gene Encoding Tumor‐rejection Antigen

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