Abstract:
:Human lysosomal acid lipase/cholesteryl ester hydrolase (hLAL) is essential for the intralysosomal metabolism of cholesteryl esters and triglycerides taken up by receptor-mediated endocytosis of lipoprotein particles. The key role of the enzyme in intracellular lipid homeostasis is illustrated by two lysosomal storage diseases inherited as autosomal recessive traits. Wolman disease, associated with deficient hLAL activity, leads to massive intracellular substrate accumulation and is always fatal in early infancy. Cholesteryl ester storage disease (CESD), in contrast, is characterized by very low levels of enzymic activity sufficient to allow survival of the affected patients into adulthood. In order to elucidate the underlying molecular defects in Wolman disease, we have characterized the hLAL gene in two female Wolman patients of German and Turkish origin by SSCP and DNA sequence analysis. Our results demonstrate that the German proband was compound heterozygous for an 8-bp deletion in exon 3 and a 2-bp deletion in exon 4 of the hLAL gene. These frameshift mutations lead to protein truncation at amino acid positions 24 and 116 and to complete loss of hydrolytic activity. The Turkish proband, in contrast, was homozygous for a G(1064)-->T substitution in exon 10 of the hLAL gene which converts the completely conserved glycine (GGG) residue at position 321 of the mature enzyme to tryptophan (TGG). In vitro expression of the hLAL(Gly(321)-->Trp) cDNA construct revealed that the amino acid replacement results in a more than 99% reduction of neutral lipid hydrolysis. The mutations provide new insights into the molecular basis of Wolman disease which is apparently more heterogeneous at the genetic level than cholesteryl ester storage disease.-Lohse, P., S. Maas, P. Lohse, A. C. Sewell, O. P. van Diggelen, and D. Seidel. Molecular defects underlying Wolman disease appear to be more heterogeneous than those resulting in cholesteryl ester storage disease.
journal_name
J Lipid Resjournal_title
Journal of lipid researchauthors
Lohse P,Maas S,Sewell AC,van Diggelen OP,Seidel Dsubject
Has Abstractpub_date
1999-02-01 00:00:00pages
221-8issue
2eissn
0022-2275issn
1539-7262journal_volume
40pub_type
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journal_title:Journal of lipid research
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journal_title:Journal of lipid research
pub_type: 临床试验,杂志文章
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pub_type: 杂志文章
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journal_title:Journal of lipid research
pub_type: 杂志文章
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journal_title:Journal of lipid research
pub_type: 杂志文章
doi:
更新日期:1999-07-01 00:00:00
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journal_title:Journal of lipid research
pub_type: 杂志文章
doi:10.1194/jlr.M070938
更新日期:2017-02-01 00:00:00
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journal_title:Journal of lipid research
pub_type: 杂志文章
doi:
更新日期:2000-07-01 00:00:00
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journal_title:Journal of lipid research
pub_type: 杂志文章
doi:
更新日期:1993-05-01 00:00:00
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journal_title:Journal of lipid research
pub_type: 杂志文章
doi:
更新日期:1970-07-01 00:00:00
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journal_title:Journal of lipid research
pub_type: 杂志文章
doi:
更新日期:1973-09-01 00:00:00
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journal_title:Journal of lipid research
pub_type: 杂志文章
doi:
更新日期:1989-04-01 00:00:00
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journal_title:Journal of lipid research
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journal_title:Journal of lipid research
pub_type: 杂志文章
doi:
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journal_title:Journal of lipid research
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doi:
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journal_title:Journal of lipid research
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journal_title:Journal of lipid research
pub_type: 杂志文章
doi:
更新日期:1987-06-01 00:00:00
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journal_title:Journal of lipid research
pub_type: 杂志文章
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更新日期:2002-02-01 00:00:00
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journal_title:Journal of lipid research
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