Identification of novel SNPs of ABCD1, ABCD2, ABCD3, and ABCD4 genes in patients with X-linked adrenoleukodystrophy (ALD) based on comprehensive resequencing and association studies with ALD phenotypes.

[adrenomyeloneuropathy]

Adrenoleukodystrophy (ALD ) is an X-linked disorder affecting primarily the white matter of the central nervous system occasionally accompanied by adrenal insufficiency . Despite the discovery of the causative gene , ABCD 1 , no clear genotype-phenotype correlations have been established . Association studies based on single nucleotide polymorphisms (SNPs ) identified by comprehensive resequencing of genes related to ABCD 1 may reveal genes modifying ALD phenotypes . We analyzed 40 Japanese patients with ALD . ABCD 1 and ABCD 2 were analyzed using a newly developed microarray-based resequencing system . ABCD 3 and ABCD 4 were analyzed by direct nucleotide sequence analysis . Replication studies were conducted on an independent French ALD cohort with extreme phenotypes . All the mutations of ABCD 1 were identified , and there was no correlation between the genotypes and phenotypes of ALD . SNPs identified by the comprehensive resequencing of ABCD 2 , ABCD 3 , and ABCD 4 were used for association studies . There were no significant associations between these SNPs and ALD phenotypes , except for the five SNPs of ABCD 4 , which are in complete disequilibrium in the Japanese population . These five SNPs were significantly less frequently represented in patients with adrenomyeloneuropathy (AMN ) than in controls in the Japanese population (p =0 .0468 ), whereas there were no significant differences in patients with childhood cerebral ALD (CCALD ). The replication study employing these five SNPs on an independent French ALD cohort , however , showed no significant associations with CCALD or pure AMN . This study showed that ABCD 2 , ABCD 3 , and ABCD 4 are less likely the disease-modifying genes , necessitating further studies to identify genes modifying ALD phenotypes .

Diseases
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Diseases presenting "complete disequilibrium in the japanese population" symptom

adrenomyeloneuropathy

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