Clinical, biochemical, molecular and therapeutic aspects of 2 new cases of 2-aminoadipic semialdehyde synthase deficiency

Tondo, Mireia; Calpena, Eduardo; Arriola, Gema; Sanz, Patricia; Martorell, Loreto; Ormazábal, Aída; Castejón, Esperanza; Palacı́n, Manuel; Ugarte, Magdalena; Espinós, Carmen; Pérez, Belén; Pérez‐Dueñas, Belén; Pérez‐Cerdá, Celia; Artuch, Rafael

doi:10.1016/j.ymgme.2013.06.021

Cited by 16 publications

(19 citation statements)

References 21 publications

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“…It is suggested that members of the ACSL gene family drive the uptake of long-chain fatty acids for β-oxidation, and are required for cold thermogenesis (Ellis et al 2010). Additionally, AASS , a gene product that catalyzes the first two steps in the lysine degradation pathway (Tondo et al 2013; Sacksteder et al 2000), is upregulated during Torpor in dwarf lemur WAT. This is important as a significant amount of metabolic energy can come from amino acid metabolism, especially during starvation conditions, as experienced by hibernating animals.…”

Section: Discussionmentioning

confidence: 99%

Gene Expression Profiling in the Hibernating Primate,Cheirogaleus Medius

et al. 2016

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Hibernation is a complex physiological response that some mammalian species employ to evade energetic demands. Previous work in mammalian hibernators suggests that hibernation is activated not by a set of genes unique to hibernators, but by differential expression of genes that are present in all mammals. This question of universal genetic mechanisms requires further investigation and can only be tested through additional investigations of phylogenetically dispersed species. To explore this question, we use RNA-Seq to investigate gene expression dynamics as they relate to the varying physiological states experienced throughout the year in a group of primate hibernators—Madagascar’s dwarf lemurs (genus Cheirogaleus). In a novel experimental approach, we use longitudinal sampling of biological tissues as a method for capturing gene expression profiles from the same individuals throughout their annual hibernation cycle. We identify 90 candidate genes that have variable expression patterns when comparing two active states (Active 1 and Active 2) with a torpor state. These include genes that are involved in metabolic pathways, feeding behavior, and circadian rhythms, as might be expected to correlate with seasonal physiological state changes. The identified genes appear to be critical for maintaining the health of an animal that undergoes prolonged periods of metabolic depression concurrent with the hibernation phenotype. By focusing on these differentially expressed genes in dwarf lemurs, we compare gene expression patterns in previously studied mammalian hibernators. Additionally, by employing evolutionary rate analysis, we find that hibernation-related genes do not evolve under positive selection in hibernating species relative to nonhibernators.

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Section: Discussionmentioning

confidence: 99%

Gene Expression Profiling in the Hibernating Primate,Cheirogaleus Medius

et al. 2016

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“…AASS is a bifunctional enzyme with two domains, lysine‐ketoglutarate reductase (LKR) and saccharopine dehydrogenase (SDH). Most individuals with AASS mutations have hyperlysinemia type I due to combined LKR and SDH deficiencies, which is biochemically characterized by hyperlysinemia with no significant or a variable saccharopinuria 11,12,20,21 . Very few cases have been described with hyperlysinemia and a pronounced saccharopinuria due to an isolated SDH defect (hyperlysinemia type II, MIM #268700).…”

Section: Introductionmentioning

confidence: 99%

Deletion of 2‐aminoadipic semialdehyde synthase limits metabolite accumulation in cell and mouse models for glutaric aciduria type 1

Leandro

Dodatko

DeVita

et al. 2020

J of Inher Metab Disea

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Glutaric aciduria type 1 (GA1) is an inborn error of lysine degradation characterized by acute encephalopathy that is caused by toxic accumulation of lysine degradation intermediates. We investigated the efficacy of substrate reduction through inhibition of 2-aminoadipic semialdehyde synthase (AASS), an enzyme upstream of the defective glutaryl-CoA dehydrogenase (GCDH), in a cell line and mouse model of GA1. We show that loss of AASS function in GCDH-deficient HEK-293 cells leads to an approximately fivefold reduction in the established GA1 clinical biomarker glutarylcarnitine. In the GA1 mouse model, deletion of Aass leads to a 4.3-, 3.8-, and 3.2-fold decrease in the glutaric acid levels in urine, brain, and liver, respectively. Parallel decreases were observed in urine and brain 3-hydroxyglutaric acid levels, and plasma, urine, and brain glutarylcarnitine levels. These in vivo data demonstrate that the saccharopine pathway is the main source of glutaric acid production in the brain and periphery of a mouse model for GA1, and support the notion that pharmacological inhibition of AASS may represent an attractive strategy to treat GA1.

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“…The next highly up-regulated gene was AASS, which encodes alpha-aminoadipic semialdehyde synthase, a bifunctional protein that catalyzes the first 2 steps in the lysine degradation pathway [25]. The role of AASS in lysine metabolism has been confirmed by earlier studies, where the inactivating mutations in the AASS gene were shown to be a cause of hyperlysinemia [26].…”

Section: Discussionmentioning

confidence: 87%

Biochemical properties of cofactor and coenzyme metabolism in porcine oviductal epithelial cells – a microarray study

Kocherova

Kulus

Dompe

et al. 2019

Medical Journal of Cell Biology

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The oviduct is a key organ responsible for ultimate oocytes maturation, transport of gametes, sperm capacitation, fertilization, as well as early embryo development. Its innermost layer, oviductal epithelium, represents a highly dynamic structure which undergoes changes in response to different physiological and pathological processes. Previously, the expression profile of genes involved in several important processes in porcine oviductal epithelial cells (OECs) during long-term primary in vitro culture. The present study further characterizes the porcine OECs model using Affymetrix microarray assay and it analyzes gene expression changes observed on the 7th, 15th and 30th day of culture. 25 genes belonging to “coenzyme metabolic process”, “cofactor biosynthetic process” and “cofactor metabolic process” GO BP terms were differentially expressed in culture. The most up-regulated genes were ALDH1L2, P2RX7, PANK1, ACSS2, SCD, AASS and PDK3. In contrast, several genes appeared to be significantly down-regulated, e.g. ACSL4 and HAAO. Considering the biological roles of the most regulated genes, it can be concluded that these changes may indicate the increased metabolic and proliferation activity of studied cells in primary in vitro culture.Running title: Cofactor and coenzyme metabolism in porcine oviductal epithelial cells

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Clinical, biochemical, molecular and therapeutic aspects of 2 new cases of 2-aminoadipic semialdehyde synthase deficiency

Cited by 16 publications

References 21 publications

Gene Expression Profiling in the Hibernating Primate,Cheirogaleus Medius

Gene Expression Profiling in the Hibernating Primate,Cheirogaleus Medius

Deletion of 2‐aminoadipic semialdehyde synthase limits metabolite accumulation in cell and mouse models for glutaric aciduria type 1

Biochemical properties of cofactor and coenzyme metabolism in porcine oviductal epithelial cells – a microarray study

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