[Molecular analysis and pathophysiology of genetic leukodystrophies].
The elucidation of the molecular genetics in genetic leukodystrophies is rapidly progressive. In 1993, genes responsible for adrenoleukodystrophy (ALD), globoid cell leukodystrophy and Canavan disease have been cloned. In this symposium, I will focus only on ALD because of the limitation of space. ALD is an X-linked recessive demyelinating disease of childhood. Adrenomyeloneuropathy (AMN) is a clinical variant of ALD. In both types of the disease, very long chain fatty acids accumulate in the body fluid and tissues of the patient. This finding suggests that there is a metabolic defect in the beta-oxidation in the peroxisome, but the primary defect has been unknown. In 1993, Mosser et al. reported a putative gene for ALD. According to the report, we obtained the cDNA from HeLa cells. Using the cDNA as the probe, we analyzed the expression of the gene in various samples of human and murine tissues. On northern blot analysis, mRNA of the gene was detected in all the tissues examined, and the amount and size of the mRNA were similar among all the tissues. We also examined the DNA and mRNA in 6 patients with ALD or AMN. On southern blot analysis, we could not detect large deletion in all the patients, while in northern blot analysis, mRNA was not detected in one patient (#163). The nucleotide sequence of mRNAs of the remaining 3 of 5 patients depicted different missense point mutations. The mutations were localized in the C-terminal regions of the gene, which are evolutionally conserved among ATP-binding protein superfamily, thereby suggesting that the mutations cause functional defect in the ALD protein.(ABSTRACT TRUNCATED AT 250 WORDS)
Kobayashi
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Department of Neurology, Faculty of Medicine, Kyushu University.
D000326:Adrenoleukodystrophy / Q000235:genetics* / Q000503:physiopathology; D000818:Animals; D004247:DNA; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008830:Microbodies / Q000378:metabolism; D017354:Point Mutation; D012333:RNA, Messenger / Q000235:genetics
D012333:RNA, Messenger; D004247:DNA