Multiple and Additive Functions of ALDH3A1 and ALDH1A1

Lassen, Natalie; Bateman, J. Bronwyn; Estey, Tia; Kuszak, J.R.; Nees, David W.; Piatigorsky, Joram; Duester, Gregg; Day, Brian J.; Huang, Jie; Hines, Lisa M.; Vasiliou, Vasilis

doi:10.1074/jbc.m702076200

Cited by 152 publications

(89 citation statements)

References 60 publications

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“…Earlier studies on sterol profiling of the affected individuals with cataract and other eye disorders with causal mutation identified in CYP51A1, CYP27A1, SC5D, DHCR7 genes clearly suggest their role in sterol biosynthetic process/pathways (Gillespie et al 2016). Further, CYP51A1 is directly connected to ALDH1A1 and MAFG, both of which are linked to cataracts (Agrawal et al 2015; Lassen et al 2007). …”

Section: Resultsmentioning

confidence: 99%

Novel phenotypes and loci identified through clinical genomics approaches to pediatric cataract

et al. 2016

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Pediatric cataract is highly heterogeneous clinically and etiologically. While mostly isolated, cataract can be part of many multisystem disorders, further complicating the diagnostic process. In this study, we applied genomic tools in the form of a multi-gene panel as well as whole-exome sequencing on unselected cohort of pediatric cataract (166 patients from 74 families). Mutations in previously reported cataract genes were identified in 58% for a total of 43 mutations, including 15 that are novel. GEMIN4 was independently mutated in families with a syndrome of cataract, global developmental delay with or without renal involvement. We also highlight a recognizable syndrome that resembles galactosemia (a fulminant infantile liver disease with cataract) caused by biallelic mutations in CYP51A1. A founder mutation in RIC1 (KIAA1432) was identified in patients with cataract, brain atrophy, microcephaly with or without cleft lip and palate. For nonsyndromic pediatric cataract, we map a novel locus in a multiplex consanguineous family on 4p15.32 where exome sequencing revealed a homozygous truncating mutation in TAPT1. We report two further candidates that are biallelically inactivated each in a single cataract family: TAF1A (cataract with global developmental delay) and WDR87 (non-syndromic cataract). In addition to positional mapping data, we use iSyTE developmental lens expression and gene-network analysis to corroborate the proposed link between the novel candidate genes and cataract. Our study expands the phenotypic, allelic and locus heterogeneity of pediatric cataract. The high diagnostic yield of clinical genomics supports the adoption of this approach in this patient group.

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Section: Resultsmentioning

confidence: 99%

Novel phenotypes and loci identified through clinical genomics approaches to pediatric cataract

et al. 2016

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“…These mice are fertile and exhibit no overt phenotype, except that aged Aldh1a1 −/− mice display ~2.4-fold higher cataract incidence than wild-type mice [75]. While ALDH1A1 primarily metabolizes retinaldehyde, it also plays a role in acetaldehyde metabolism.…”

Section: Mouse Models With Genetic Deficiencies In Acetaldehyde-mmentioning

confidence: 99%

Transgenic Mouse Models for Alcohol Metabolism, Toxicity, and Cancer

Heit

Dong

Chen

et al. 2014

Advances in Experimental Medicine and Biology

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Alcohol abuse leads to tissue damage including a variety of cancers; however, the molecular mechanisms by which this damage occurs remains to be fully understood. The primary enzymes involved in ethanol metabolism include alcohol dehydrogenase (ADH), cytochrome P450 isoform 2E1, (CYP2E1), catalase (CAT), and aldehyde dehydrogenases (ALDH). Genetic polymorphisms in human genes encoding these enzymes are associated with increased risks of alcohol-related tissue damage, as well as differences in alcohol consumption and dependence. Oxidative stress resulting from ethanol oxidation is one established pathogenic event in alcohol-induced toxicity. Ethanol metabolism generates free radicals, such as reactive oxygen species (ROS) and reactive nitrogen species (RNS), and has been associated with diminished glutathione (GSH) levels as well as changes in other antioxidant mechanisms. In addition, the formation of protein and DNA adducts associated with the accumulation of ethanol-derived aldehydes can adversely affect critical biological functions and thereby promote cellular and tissue pathology. Animal models have proven to be valuable tools for investigating mechanisms underlying pathogenesis caused by alcohol. In this review, we provide a brief discussion on several animal models with genetic defects in alcohol metabolizing enzymes and GSH synthesizing enzymes and their relevance to alcohol research.

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“…CYP26A1 also has 2-to 10-fold retinaldehyde, including aldehydes derived from lipid peroxidation. In fact, ALDH1A1 plays a crucial role in protection of the mouse eye lens and cornea from lipid peroxidation aldehydes and cataract formation induced by oxidative stress, as demonstrated using various Aldh1a1 Ϫ / Ϫ mouse models ( 111 ).…”

Section: Cyp26 Familymentioning

confidence: 99%

Enzymology of retinoic acid biosynthesis and degradation

Kedishvili

2013

Journal of Lipid Research

170

165

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This article is available online at http://www.jlr.org ( 10 ), and regulation of energy homeostasis ( 11,12 ). atRA exerts its actions by serving as an activating ligand of nuclear atRA receptors [retinoid acid receptor (RAR) ␣ , RAR ␤ , and RAR ␥ ] and peroxisome proliferator-activated receptors (PPAR) ␤ / ␦ , which form heterodimers with retinoid X receptors ( 13,14 ). The actions of the RARs are described in more detail in this thematic series by RochetteEgly and colleagues. The concentration of atRA during embryonic development is tightly controlled in a spatial and temporal manner, and in adult tissues, it is maintained within a very narrow range that is specifi c for each given tissue. If the control mechanisms fail and the concentration of atRA exceeds or falls below the optimal range, tissues and cells undergo pathophysiological changes that in most severe cases can lead to disease. Thus, the maintenance of optimal atRA levels is essential for life. This review focusses on recent fi ndings regarding the mechanisms that control atRA homeostasis, with specifi c emphasis on the enzymes involved in atRA biosynthesis and degradation. All-trans -retinoic acid (atRA) is a highly potent derivative of vitamin A that is required for virtually all essential physiological processes and functions because of its involvement in transcriptional regulation of over 530 different genes ( 1, 2 ). For example, atRA is necessary for differentiation and development of fetal and adult tissues, stem cell differentiation, and apoptosis ( 3-7 ), and for support of reproductive functions ( 8, 9 ), immune response

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Multiple and Additive Functions of ALDH3A1 and ALDH1A1

Cited by 152 publications

References 60 publications

Novel phenotypes and loci identified through clinical genomics approaches to pediatric cataract

Novel phenotypes and loci identified through clinical genomics approaches to pediatric cataract

Transgenic Mouse Models for Alcohol Metabolism, Toxicity, and Cancer

Enzymology of retinoic acid biosynthesis and degradation

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