X-linked adrenoleukodystrophy phenotype is independent of ABCD2 genotype

Maier, Esther M.; Mayerhofer, Peter; Asheuer, Muriel; Köhler, Wolfgang; Rothe, Martina; Muntau, Ania C.; Roscher, Adelbert A.; Holzinger, Andreas; Aubourg, Patrick; Berger, Johannes

doi:10.1016/j.bbrc.2008.09.092

Cited by 26 publications

(18 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…While its function is unknown, ABCD2 is the closest homologue of ABCD1, the mutation of which is the well known cause of Zellweger Syndrome [29]. However, mutation in ABCD2 has been shown not to confer the same loss-of-function-related disease state [29,30]. ABCD2 has also been shown to interact directly with PEX19 (peroxisomal biogenesis factor 19) [31], β-catenin, and TCF-4 [32].…”

Section: Discussionmentioning

confidence: 99%

Integrative analyses of genetic variation, epigenetic regulation, and the transcriptome to elucidate the biology of platinum sensitivity

LaCroix

Gamazon²,

Lenkala

et al. 2014

BMC Genomics

View full text Add to dashboard Cite

BackgroundUsing genome-wide genetic, gene expression, and microRNA expression (miRNA) data, we developed an integrative approach to investigate the genetic and epigenetic basis of chemotherapeutic sensitivity.ResultsThrough a sequential multi-stage framework, we identified genes and miRNAs whose expression correlated with platinum sensitivity, mapped these to genomic loci as quantitative trait loci (QTLs), and evaluated the associations between these QTLs and platinum sensitivity. A permutation analysis showed that top findings from our approach have a much lower false discovery rate compared to those from a traditional GWAS of drug sensitivity. Our approach identified five SNPs associated with 10 miRNAs and the expression level of 15 genes, all of which were associated with carboplatin sensitivity. Of particular interest was one SNP (rs11138019), which was associated with the expression of both miR-30d and the gene ABCD2, which were themselves correlated with both carboplatin and cisplatin drug-specific phenotype in the HapMap samples. Functional study found that knocking down ABCD2 in vitro led to increased apoptosis in ovarian cancer cell line SKOV3 after cisplatin treatment. Over-expression of miR-30d in vitro caused a decrease in ABCD2 expression, suggesting a functional relationship between the two.ConclusionsWe developed an integrative approach to the investigation of the genetic and epigenetic basis of human complex traits. Our approach outperformed standard GWAS and provided hints at potential biological function. The relationships between ABCD2 and miR-30d, and ABCD2 and platin sensitivity were experimentally validated, suggesting a functional role of ABCD2 and miR-30d in sensitivity to platinating agents.

show abstract

Section: Discussionmentioning

confidence: 99%

Integrative analyses of genetic variation, epigenetic regulation, and the transcriptome to elucidate the biology of platinum sensitivity

LaCroix

Gamazon²,

Lenkala

et al. 2014

BMC Genomics

View full text Add to dashboard Cite

show abstract

“…Because the accumulation of VLCFA triggers an infl ammatory response associated with progressive demyelination in X-ALD ( 19 ), a decrease in the VLCFA content may be benefi cial for the patients. However, the other ALDP-related transporter gene, ABCD2, is not mutated in X-ALD patients, and the X-ALD phenotype is independent of the ABCD2 genotype ( 68 ). Our recent observation of an inverse correlation between the VLCFA content and the expression of Abcd2/ALDRP and a greater accumulation of VLCFAs following silencing for both Abcd1 and Abcd2 in mouse primary astrocyte cultures ( 19 ), suggests that Abcd1 and Abcd2 have overlapping functions in the metabolism of VLCFA and related compounds.…”

Section: Discussionmentioning

confidence: 99%

HDAC inhibitor SAHA normalizes the levels of VLCFAs in human skin fibroblasts from X-ALD patients and downregulates the expression of proinflammatory cytokines in Abcd1/2-silenced mouse astrocytes

Singh

Khan

Singh

2011

Journal of Lipid Research

View full text Add to dashboard Cite

This article is available online at http://www.jlr.org Supplementary key words peroxisome • very long chain FA • glia • nitric oxide • cytokine • suberoylanilide hydroxamic acid • X-adrenoleukodystrophy X-adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder, with an incidence of approximately 1:17,000 ( 1, 2 ). It is a postnatal progressive demyelinating disorder that primarily affects nervous system white matter and axons, the adrenal cortex, and testis ( 3-5 ). The biochemical signature of X-ALD is increased levels of saturated straight-chain very long chain FAs (VLCFAs; >22:0). VLCFA accumulates in all tissues and lipid classes; however, the degree of accumulation is higher in the cholesterol ester and sphingolipid fractions of brain white matter and adrenal cortex ( 6 ). The elevation of VLCFAs is the consequence of reduced VLCFA peroxisomal ␤ -oxidation ( 7 ) and/or increased activity of FA elongases ( 8, 9 ). The ALD gene (ABCD1), identifi ed by positional cloning ( 10 ), encodes a protein that is related to the peroxisomal ATP binding cassette (ABCD) transmembrane transporter proteins ( 11,12 ). The function of the adrenoleukodystrophy protein (ALDP) and its role in VLCFA metabolism and in the pathogenesis of X-ALD is not well understood at present. However, the VLCFA, especially C26:0, has been documented to cause metabolic alterations leading to membrane perturbation, redox imbalance ( 13 ), and changes in membrane lipid composition ( 14-18 ), as well as the induction of infl ammatory mediators in cultured astrocytes ( 19 ). This study was supported in part by grants from the National Institutes of Health (Grants NS-22576, NS-37766, C06 RR-018823, and C06 RR-015455, and VA merit award BX1072-01. Its Abbreviations: ALDP, adrenoleukodystrophy protein; ALDRP, adrenoleukodystrophy-related protein; AMN, adrenomyeloneuropathy; BBB, blood-brain barrier; cALD, cerebral adrenoleukodystrophy; FAME, FA methyl ester; HDAC, histone deacetylase; iNOS, inducible nitric oxide synthase; 5-LOX, 5-lipoxygenase; PA, phenylacetate; PBA, phenylbutyrate; ROS, reactive oxygen species; SAHA, suberoylanilide hydroxamic acid; TNF-␣ , tumor necrosis factor-␣ ; X-ALD, X-adrenoleukodystrophy; VLCFA, very long chain FA.

show abstract

“…Mice lacking Abcd1 expression exhibit an AMN-like phenotype, axonal degeneration, and mitochondrial deficits, but do not develop cerebral inflammatory disease suggesting that mutations within ABCD1 cause AMN [6]. Therefore, genetic, epigenetic, environmental, and/or stochastic factors may contribute to the phenotypic heterogeneity of XALD [5]. ABCD2, ABCD3, and ABCD4, genes related to ABCD1 by sequence similarity, are not genetic modifiers of XALD [5,7].…”

Section: Introductionmentioning

confidence: 93%

“…Therefore, genetic, epigenetic, environmental, and/or stochastic factors may contribute to the phenotypic heterogeneity of XALD [5]. ABCD2, ABCD3, and ABCD4, genes related to ABCD1 by sequence similarity, are not genetic modifiers of XALD [5,7]. An insertion in the methionine metabolism gene cystathionine-beta-synthase (CBS c.844_845ins68) has been associated with protection against cerebral demyelination [8].…”

Section: Introductionmentioning

confidence: 98%

“…Different phenotypes, including CCALD and AMN, commonly occur within the same family, among individuals with identical ABCD1 genotypes, including patients with the complete absence of ABCD1 protein expression, and among a few monozygous twin pairs [5]. Mice lacking Abcd1 expression exhibit an AMN-like phenotype, axonal degeneration, and mitochondrial deficits, but do not develop cerebral inflammatory disease suggesting that mutations within ABCD1 cause AMN [6].…”

Section: Introductionmentioning

confidence: 98%

See 1 more Smart Citation

SOD2 as a potential modifier of X-linked adrenoleukodystrophy clinical phenotypes

2012

View full text Add to dashboard Cite

X-linked adrenoleukodystrophy (XALD), a neurological disorder caused by mutations in the peroxisomal membrane protein gene ABCD1, presents as a rapidly progressing, inflammatory cerebral demyelination (cerebral cases) or a slowly progressing, distal axonopathy (non-cerebral cases). Specific ABCD1 defects do not explain this significant phenotypic variation. Patients have increased plasma and tissue very long chain fatty acid levels and increased cellular oxidative stress and oxidative damage. Superoxide dismutase 2 (SOD2), at candidate modifier locus 6q25.3, detoxifies superoxide radicals protecting against oxidative stress and damage. We tested an SOD2 variant C47T (Ala16Val) associated with reduced enzymatic activity as a potential modifier gene of cerebral demyelinating disease by comparing 117 cerebral XALD cases with 105 non-cerebral XALD cases. The hypoactive valine allele of the variant was associated with cerebral disease under a dominant model in the full data set (p = 0.04; ORT* = 1.90, 95% CI 1.01-3.56) and the non-childhood cerebral disease subset (p = 0.03; ORT* = 2.47, 95% CI 1.08-5.61). Three tag SNPs were genotyped to test for additional SNP or haplotype associations. A common haplotype, GTAC, which included the SOD2 valine allele, was associated with cerebral disease in the full data set (p = 0.03; OR = 1.75, 95% CI 1.11-2.75) and the non-childhood cerebral disease subset (p = 0.008; OR = 2.20, 95% CI 1.27-3.83). There was no association between childhood cerebral XALD and the C47T variant or the GTAC haplotype. Thus, reduced SOD2 activity may contribute to the development of cerebral demyelination in adolescent and adult XALD patients.

show abstract

X-linked adrenoleukodystrophy phenotype is independent of ABCD2 genotype

Cited by 26 publications

References 31 publications

Integrative analyses of genetic variation, epigenetic regulation, and the transcriptome to elucidate the biology of platinum sensitivity

Integrative analyses of genetic variation, epigenetic regulation, and the transcriptome to elucidate the biology of platinum sensitivity

HDAC inhibitor SAHA normalizes the levels of VLCFAs in human skin fibroblasts from X-ALD patients and downregulates the expression of proinflammatory cytokines in Abcd1/2-silenced mouse astrocytes

SOD2 as a potential modifier of X-linked adrenoleukodystrophy clinical phenotypes

Contact Info

Product

Resources

About