Abstract
X-linked adrenoleukodystrophy (X-ALD) is characterized by marked phenotypic variation ranging from adrenomyeloneuropathy (AMN) to childhood cerebral ALD (CCALD). X-ALD is caused by mutations in the ABCD1 gene, but no genotype-phenotype correlation has been established so far and modifier gene variants are suspected to modulate phenotypes. Specific classes of lipids, enriched in very long-chain fatty acids that accumulate in plasma and tissues from X-ALD patients are suspected to be involved in the neuroinflammatory process of CCALD. CD1 proteins are lipid- antigen presenting molecules encoded by five CD1 genes in human (CD1A-E). Association studies with 23 tag SNPs covering the CD1 locus was performed in 52 patients with AMN and 87 patients with CCALD. The minor allele of rs973742 located 4-kb downstream from CD1D was significantly more frequent in AMN patients (χ2 = 7.6; P = 0.006). However, this association was no longer significant after Bonferroni correction for multiple testing. The other polymorphisms of the CD1 locus did not reveal significant association. Further analysis of other CD1D polymorphisms did not detect stronger association with X-ALD phenotypes. Although the association with rs973742 warrants further investigations, these results indicate that the genetic variants of CD1 genes do not contribute markedly to the phenotypic variance of X-ALD.
Highlights
X-linked adrenoleukodystrophy (X-ALD; MIM# 300100) is a progressive neurodegenerative disease that is caused by mutations in the ABCD1 gene, encoding ALD protein (ALDP), an (ATP)-binding-cassette (ABC) transporter located in the peroxisomal membrane [1]
We observed that the five CD1 genes were included in a single block of linkage disequilibrium (LD), excluding LD of CD1 genes polymorphisms with polymorphisms of surrounding genes
Three tag SNPs showed evidence of allelic associations with X-ALD phenotypes at a 0.05 significance level (Table 1): rs973742 G/A (x2 = 7.6; P = 0.006; empirical P = 0.008) located 4-kb downstream from the 39 region of CD1D; rs3181082 C/T (x2 = 5.3; P = 0.028; empirical P = 0.031) and rs2317955 G/T (x2 = 4.4; P = 0.043; empirical P = 0.054) which are in LD (r2 = 0.96), and located in the upstream region of CD1B
Summary
X-linked adrenoleukodystrophy (X-ALD; MIM# 300100) is a progressive neurodegenerative disease that is caused by mutations in the ABCD1 gene, encoding ALD protein (ALDP), an (ATP)-binding-cassette (ABC) transporter located in the peroxisomal membrane [1]. Based on cross complementation in yeast, it is suggested that ALDP is active as a homodimer and is involved in the transport of very long-chain fatty (VLCF) acylCoA esters across the peroxisomal membrane [2]. ALDP deficiency results in increased levels of VLCFacyl-CoA esters in the cytosol and all X-ALD patients accumulate saturated straight very-long-chain fatty acids (VLCFA) in their plasma and tissues [3]. As X-ALD males in the same family may express different phenotypes, it is clear that mutations of the ABCD1 gene does not account for the disease variability. No correlation between X-ALD phenotype and levels of VLCFA accumulation observed in plasma and fibroblasts from X-ALD patients has been demonstrated either
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