A 6-bp deletion at the splice donor site of the first intron resulted in aberrant splicing using a cryptic splice site within exon 1 in a patient with succinyl-CoA: 3-Ketoacid CoA transferase (SCOT) deficiency

Fukao, Toshiyuki; Sakurai, Satomi; Rolland, Marie-Odile; Zabot, M. T.; Schulze, Andreas; Yamada, Keitaro; Kondo, Naomi

doi:10.1016/j.ymgme.2006.04.014

Cited by 19 publications

(10 citation statements)

References 12 publications

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“…Therefore, while the data on ketone body metabolism in heart failure are currently very limited, diminished myocardial ketone body oxidation could promote pathological outcomes. Of the identified CoA transferasedeficient patients, two were reported to present with dilated cardiomyopathy (63,126,210). Future studies in humans that specifically measure CoA transferase function and ketone body oxidation in cardiomyopathic states, complemented by mechanistic studies using tissue-selective genetic rodent models, will be required to definitively determine how myocardial ketone body metabolism changes in pathophysiological states and the contexts in which myocardial ketone body utilization may be adaptive or maladaptive.…”

Section: Ketone Bodies and Myocardial Diseasementioning

confidence: 99%

Ketone body metabolism and cardiovascular disease

Cotter

Schugar

Crawford

2013

American Journal of Physiology-Heart and Circulatory Physiology

366

304

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Ketone bodies are metabolized through evolutionarily conserved pathways that support bioenergetic homeostasis, particularly in brain, heart, and skeletal muscle when carbohydrates are in short supply. The metabolism of ketone bodies interfaces with the tricarboxylic acid cycle, β-oxidation of fatty acids, de novo lipogenesis, sterol biosynthesis, glucose metabolism, the mitochondrial electron transport chain, hormonal signaling, intracellular signal transduction pathways, and the microbiome. Here we review the mechanisms through which ketone bodies are metabolized and how their signals are transmitted. We focus on the roles this metabolic pathway may play in cardiovascular disease states, the bioenergetic benefits of myocardial ketone body oxidation, and prospective interactions among ketone body metabolism, obesity, metabolic syndrome, and atherosclerosis. Ketone body metabolism is noninvasively quantifiable in humans and is responsive to nutritional interventions. Therefore, further investigation of this pathway in disease models and in humans may ultimately yield tailored diagnostic strategies and therapies for specific pathological states.

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Section: Ketone Bodies and Myocardial Diseasementioning

confidence: 99%

Ketone body metabolism and cardiovascular disease

Cotter

Schugar

Crawford

2013

American Journal of Physiology-Heart and Circulatory Physiology

366

304

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“…Although tissuespecific SCOT-KO models have utility in determining the metabolic roles of ketolysis within individual tissues, naturally occurring variations in ketone body oxidative capacity in humans likely affect all ketolytic cell types (7,19,20,35,37,46,54,56 ϩ/Ϫ littermate mice were exposed to ketogenic milieus at 6 wk of age. First, to measure the consequences of acute ketosis, male Oxct1 ϩ/Ϫ and wild-type littermate control mice were subjected to a 48-h period of starvation.…”

Section: Restoration Of Myocardial Ketone Body Oxidation In Germline mentioning

confidence: 99%

Successful adaptation to ketosis by mice with tissue-specific deficiency of ketone body oxidation

Cotter

Schugar

Wentz

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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Cotter DG, Schugar RC, Wentz AE, d'Avignon DA, Crawford PA. Successful adaptation to ketosis by mice with tissuespecific deficiency of ketone body oxidation. Am J Physiol Endocrinol Metab 304: E363-E374, 2013. First published December 11, 2012; doi:10.1152/ajpendo.00547.2012.-During states of low carbohydrate intake, mammalian ketone body metabolism transfers energy substrates originally derived from fatty acyl chains within the liver to extrahepatic organs. We previously demonstrated that the mitochondrial enzyme coenzyme A (CoA) transferase [succinyl-CoA:3-oxoacid CoA transferase (SCOT), encoded by nuclear Oxct1] is required for oxidation of ketone bodies and that germline SCOTknockout (KO) mice die within 48 h of birth because of hyperketonemic hypoglycemia. Here, we use novel transgenic and tissue-specific SCOT-KO mice to demonstrate that ketone bodies do not serve an obligate energetic role within highly ketolytic tissues during the ketogenic neonatal period or during starvation in the adult. Although transgene-mediated restoration of myocardial CoA transferase in germline SCOT-KO mice is insufficient to prevent lethal hyperketonemic hypoglycemia in the neonatal period, mice lacking CoA transferase selectively within neurons, cardiomyocytes, or skeletal myocytes are all viable as neonates. Like germline SCOT-KO neonatal mice, neonatal mice with neuronal CoA transferase deficiency exhibit increased cerebral glycolysis and glucose oxidation, and, while these neonatal mice exhibit modest hyperketonemia, they do not develop hypoglycemia. As adults, tissue-specific SCOT-KO mice tolerate starvation, exhibiting only modestly increased hyperketonemia. Finally, metabolic analysis of adult germline Oxct1 ϩ/Ϫ mice demonstrates that global diminution of ketone body oxidation yields hyperketonemia, but hypoglycemia emerges only during a protracted state of low carbohydrate intake. Together, these data suggest that, at the tissue level, ketone bodies are not a required energy substrate in the newborn period or during starvation, but rather that integrated ketone body metabolism mediates adaptation to ketogenic nutrient states.coenzyme A transferase; glucose homeostasis; ketone body metabolism; mouse models of ketolytic deficiency ADAPTATION TO LIMITED CARBOHYDRATE availability and increased fatty acid supply, as encountered during the initial transition to extrauterine life, starvation, and adherence to low-carbohydrate diets, requires shifts in metabolic substrate utilization (11,25,40,52). While many organs are poised to meet the bioenergetic demands imposed by fat-dominated energy economies, neurons do not effectively derive high-energy phosphates from fatty acids (16,71). Thus, provision of alternate fuel sources may be required to preserve bioenergetic homeostasis within some tissues when carbohydrates are limiting. Ketone body metabolism supports this function by oxidizing hepatic fatty acyl-coenzyme A species (acyl-CoAs) to water-soluble four-carbon ketone body intermediates (via ketogenesis) that are shared with...

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“…SCOT deficiency (MIM #245050), clinically characterized by episodes of severe ketoacidosis, is an autosomal recessive inborn error of metabolism, first described in 1972 [Tildon and Cornblath, 1972]. Since the first description of SCOT deficiency, fewer than 30 affected probands have been reported including personal communications [Baric et al, 2001;Berry et al, 2001;Cornblath et al, 1971;Fukao et al, 1996Fukao et al, , 2000Fukao et al, , 2004Fukao et al, , 2006Fukao et al, , 2007Fukao et al, , 2010Fukao et al, , 2011Kassovska-Bratinova et al, 1996;Longo et al, 2004;Merron and Akhtar, 2009;Niezen-Koning et al, 1997;Perez-Cerda et al, 1992;Pretorius et al, 1996;Rolland et al, 1998;Sakazaki et al, 1995;Snyderman et al, 1998;Song et al, 1998;Tildon and Cornblath, 1972;Yamada et al, 2007].…”

Section: Introductionmentioning

confidence: 99%

Molecular Basis of Two-Exon Skipping (Exons 12 and 13) by c.1248+5g>a inOXCT1Gene: Study on Intermediates ofOXCT1Transcripts in Fibroblasts

et al. 2013

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The molecular basis of simultaneous two-exon skipping induced by a splice-site mutation has yet to be completely explained. The splice donor site mutation c.1248+5g>a (IVS13) of the OXCT1 gene resulted predominantly in skipping of exons 12 and 13 in fibroblasts from a patient (GS23) with succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency. We compared heteronuclear RNA (hnRNA) intermediates between controls' and GS23's fibroblasts. Our strategy was to use RT-PCR of hnRNA to detect the presence or absence of spliced exon clusters in RNA intermediates (SECRIs) comprising sequential exons. Our initial hypothesis was that a SECRI comprising exons 12 and 13 was formed first followed by skipping of this SECRI in GS23 cells. However, such a pathway was revealed to be not a major one. Hence, we compared the intron removal of SCOT transcript between controls and GS23. In controls, intron 11 was the last intron to be spliced and the removal of intron 12 was also rather slow and occurred after the removal of intron 13 in a major pathway. However, the mutation in GS23 cells resulted in retention of intron 13, thus causing the retention of introns 12 and 11. This "splicing paralysis" may be solved by skipping the whole intron 11-exon 12-intron 12-exon 13-mutated intron 13, resulting in skipping of exons 12 and 13.

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A 6-bp deletion at the splice donor site of the first intron resulted in aberrant splicing using a cryptic splice site within exon 1 in a patient with succinyl-CoA: 3-Ketoacid CoA transferase (SCOT) deficiency

Cited by 19 publications

References 12 publications

Ketone body metabolism and cardiovascular disease

Ketone body metabolism and cardiovascular disease

Successful adaptation to ketosis by mice with tissue-specific deficiency of ketone body oxidation

Molecular Basis of Two-Exon Skipping (Exons 12 and 13) by c.1248+5g>a inOXCT1Gene: Study on Intermediates ofOXCT1Transcripts in Fibroblasts

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