CYP4F2 affects phenotypic outcome in adrenoleukodystrophy by modulating the clearance of very long-chain fatty acids

Engen, Catherine E. van; Ofman, Rob; Dijkstra, Inge M. E.; Goethem, Tessa Jacobs van; Verheij, Eveline; Varin, Jennifer; Vidaud, Michel; Wanders, Ronald J. A.; Aubourg, Patrick; Kemp, Stephan; Barbier, Mathieu

doi:10.1016/j.bbadis.2016.07.006

Cited by 17 publications

(13 citation statements)

References 56 publications

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“…There is considerable interest in finding genes that modify the phenotype of ALD. A polymorphism in CYP4F2, the gene that is responsible for peroxisomal ω‐oxidation of VLCFA to very long‐chain dicarboxylic acids was found to increase the risk of development of childhood onset CALD by decreasing the clearance of VLCFA through ω‐oxidation (van Engen et al, ). Eleven microRNAs were identified that had different expression for CALD and AMN and one of them, MiR‐196a, was found to inhibit the expression of two inflammatory signaling factors as well as ELOVL1 (Shah & Singh, ).…”

Section: Cell‐ and Tissue‐specific Pathologymentioning

confidence: 99%

X‐linked adrenoleukodystrophy: Pathology, pathophysiology, diagnostic testing, newborn screening and therapies

Turk

Theda

Fatemi

et al. 2020

Intl J of Devlp Neuroscience

131

113

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Adrenoleukodystrophy (ALD) is a rare X‐linked disease caused by a mutation of the peroxisomal ABCD1 gene. This review summarizes our current understanding of the pathogenic cell‐ and tissue‐specific roles of lipid species in the context of experimental therapeutic strategies and provides an overview of critical historical developments, therapeutic trials and the advent of newborn screening in the USA. In ALD, very long‐chain fatty acid (VLCFA) chain length‐dependent dysregulation of endoplasmic reticulum stress and mitochondrial radical generating systems inducing cell death pathways has been shown, providing the rationale for therapeutic moiety‐specific VLCFA reduction and antioxidant strategies. The continuing increase in newborn screening programs and promising results from ongoing and recent therapeutic investigations provide hope for ALD.

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Section: Cell‐ and Tissue‐specific Pathologymentioning

confidence: 99%

X‐linked adrenoleukodystrophy: Pathology, pathophysiology, diagnostic testing, newborn screening and therapies

Turk

Theda

Fatemi

et al. 2020

Intl J of Devlp Neuroscience

131

113

View full text Add to dashboard Cite

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“…In the present study, we first reported that LO has remarkable effects on the hepatic gene expression involved in peroxisomal fatty acid b-oxidation and microsomal fatty acid elongation. More recently, van Engen et al showed that mutation of Cyp4f2 decreases the conversion of VLCFA into very long chain dicarboxylic acids by o-oxidation (van Engen et al 2016). As the o-oxidation is a potential escape route for the deficient peroxisomal VLCFA b-oxidation in ALD, it is interesting whether LO induces expression of Cyp4f2 gene.…”

Section: Changes In Hepatic Gene Expression In Lo-treated Micementioning

confidence: 99%

Effect of Lorenzo’s Oil on Hepatic Gene Expression and the Serum Fatty Acid Level in abcd1-Deficient Mice

et al. 2017

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Lorenzo's oil is known to decrease the saturated very long chain fatty acid (VLCFA) level in the plasma and skin fibroblasts of X-linked adrenoleukodystrophy (ALD) patients. However, the involvement of Lorenzo's oil in in vivo fatty acid metabolism has not been well elucidated. To investigate the effect of Lorenzo's oil on fatty acid metabolism, we analyzed the hepatic gene expression together with the serum fatty acid level in Lorenzo's oiltreated wild-type and abcd1-deficient mice. The change in the serum fatty acid level in Lorenzo's oil-treated abcd1-defcient mice was quite similar to that in the plasma fatty acid level in ALD patients supplemented with Lorenzo's oil. In addition, we found that the hepatic gene expression of two peroxisomal enzymes, Dbp and Scp2, and three microsomal enzymes, Elovl1, 2, and 3, were significantly stimulated by Lorenzo's oil. Our findings indicate that Lorenzo's oil activates hepatic peroxisomal fatty acid boxidation at the transcriptional level. In contrast, the transcriptional stimulation of Elovl1, 2, and 3 by Lorenzo's oil does not cause changes in the serum fatty acid level. It seems likely that the inhibition of these elongation activities by Lorenzo's oil results in a decrease in saturated VLCFA. Thus, these results not only contribute to a clarification of the mechanism by which the saturated VLCFA level is reduced in the serum of ALD patients by Lorenzo's oiltreatment, but also suggest the development of a new therapeutic approach to peroxisomal b-oxidation enzyme deficiency, especially mild phenotype of DBP deficiency.

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“…We first focused on alleles which emerged from previous modifier studies to see if they are confirmed. Proposed modifier alleles from target gene studies have identified two candidates within ELOVL1 (rs839765) and CYP4F2 (rs2108622) (Kemp et al, 2012;van Engen et al, 2016). Within this cohort, those modifier alleles do not segregate with ALD phenotype (Table 1), nor are the genotypes shared or lacking in the confidently phenotyped CALD patients.…”

Section: Discordant Genotype Analysis For the Identification Of A Modmentioning

confidence: 94%

Multi-Omic Approach to Identify Phenotypic Modifiers Underlying Cerebral Demyelination in X-Linked Adrenoleukodystrophy

Richmond

Kloet

Vaz

et al. 2020

Front. Cell Dev. Biol.

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X-linked adrenoleukodystrophy (ALD) is a peroxisomal metabolic disorder with a highly complex clinical presentation. ALD is caused by mutations in the ABCD1 gene, and is characterized by the accumulation of very long-chain fatty acids in plasma and tissues. Disease-causing mutations are 'loss of function' mutations, with no prognostic value with respect to the clinical outcome of an individual. All male patients with ALD develop spinal cord disease and a peripheral neuropathy in adulthood, although age of onset is highly variable. However, the lifetime prevalence to develop progressive white matter lesions, termed cerebral ALD (CALD), is only about 60%. Early identification of transition to CALD is critical since it can be halted by allogeneic hematopoietic stem cell therapy only in an early stage. The primary goal of this study is to identify molecular markers which may be prognostic of cerebral demyelination from a simple blood sample, with the hope that blood-based assays can replace the current protocols for diagnosis. We collected six well-characterized brother pairs affected by ALD and discordant for the presence of CALD and performed multi-omic profiling of blood samples including genome, epigenome, transcriptome, metabolome/lipidome, and proteome profiling. In our analysis we identify discordant genomic alleles present across all families as well as differentially abundant molecular features across the omics technologies. The analysis was focused on univariate modeling to discriminate the two phenotypic groups, but was unable to identify statistically significant candidate molecular markers. Our study

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CYP4F2 affects phenotypic outcome in adrenoleukodystrophy by modulating the clearance of very long-chain fatty acids

Cited by 17 publications

References 56 publications

X‐linked adrenoleukodystrophy: Pathology, pathophysiology, diagnostic testing, newborn screening and therapies

X‐linked adrenoleukodystrophy: Pathology, pathophysiology, diagnostic testing, newborn screening and therapies

Effect of Lorenzo’s Oil on Hepatic Gene Expression and the Serum Fatty Acid Level in abcd1-Deficient Mice

Multi-Omic Approach to Identify Phenotypic Modifiers Underlying Cerebral Demyelination in X-Linked Adrenoleukodystrophy

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