X-linked adrenoleukodystrophy: Genes, mutations, and phenotypes

被引:145
作者
Smith, KD
Kemp, S
Braiterman, LT
Lu, JF
Wei, HM
Geraghty, M
Stetten, G
Bergin, JS
Pevsner, J
Watkins, PA
机构
[1] Johns Hopkins Univ, Sch Med, Kennedy Krieger Inst, Baltimore, MD 21205 USA
[2] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA
[3] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA
[4] Johns Hopkins Univ, Sch Med, Dept Gynecol & Obstet, Baltimore, MD 21205 USA
[5] Johns Hopkins Univ, Sch Med, Inst Med Genet, Baltimore, MD 21205 USA
关键词
adrenoleukodystrophy; peroxisomes; ABC transporters; mutations; genotype/phenotype; VLCS;
D O I
10.1023/A:1022535930009
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
X-linked adrenoleukodystrophy (X-ALD) is a complex and perplexing neurodegenerative disorder. The metabolic abnormality, elevated levels of very long-chain fatty acids in tissues and plasma, and the biochemical defect, reduced peroxisomal very long-chain acyl-CoA synthetase (VLCS) activity, are ubiquitous features of the disease; However, clinical manifestations are highly variable with regard to time of onset, site of initial pathology and rate of progression. In addition, the abnormal gene in X-ALD is not the gene for VLCS. Rather, it encodes a peroxisomal membrane protein with homology to the ATP-binding cassette (ABC) transmembrane transporter superfamily of proteins. The X-ALD protein (ALDP) is closely related to three other peroxisomal membrane ABC proteins. In this report we summarize all known X-ALD mutations and establish the lack of an X-ALD genotype/phenotype correlation. We compare the evolutionary relationships among peroxisomal ABC proteins, demonstrate that ALDP forms homodimers with itself and heterodimers with other peroxisomal ABC proteins and present cDNA complementation studies suggesting that the peroxisomal ABC proteins have overlapping functions. We also establish that there are at least two peroxisomal VLCS activities, one that is ALDP dependent and one that is ALDP independent. Finally, we discuss variable expression of the peroxisomal ABC proteins and ALDP independent VLCS in relation to the variable clinical presentations of X-ALD.
引用
收藏
页码:521 / 535
页数:15
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