title: Characterization of lysosomal acid lipase mutations in the signal peptide and mature polypeptide region causing Wolman disease.
abstract: Wolman disease results from an inherited deficiency of lysosomal acid lipase (LAL; EC 3.1.1.13). This enzyme is essential for the hydrolysis of cholesteryl esters and triacylglycerols derived from endocytosed lipoproteins. Because of a complete absence of LAL activity, Wolman patients accumulate progressive amounts of cholesteryl esters and triacylglycerols in affected tissues. To investigate the nature of the genetic defects causing this disease, mutations in the LAL gene from three subjects of Moslem-Arab and Russian descent living in Israel were determined. Two homozygotes for a novel 1-bp deletion introducing a premature in-frame termination codon at amino acid position 106 (S106X) were identified. A third subject was a homozygote for a G-5R signal peptide substitution and a G60V missense mutation. The functional significance of these mutations was tested by in vitro expression of single and double mutants in Spodoptera frugiperda cells. Single mutants G60V and S106X and double mutant G-5R/G60V displayed a virtual absence of lipase activity in cell extracts and culture medium. Signal peptide mutant G-5R retained lipase activity in cell extracts and showed a drastically reduced enzyme activity in culture supernatant, indicating that the mutation may affect secretion of active enzyme from cells. These results support the notion that Wolman disease is a genetically heterogeneous disorder of lipid metabolism.
authors: Department of Medicine, University Hospital Eppendorf, 20246 Hamburg, Germany.
authors: O
authors: O
authors: Zschenker
authors: N
authors: N
authors: Jung
authors: J
authors: J
authors: Rethmeier
authors: S
authors: S
authors: Trautwein
authors: S
authors: S
authors: Hertel
authors: M
authors: M
authors: Zeigler
authors: D
authors: D
authors: Ameis
mesh_terms: D000818:Animals; D002788:Cholesterol Esters / Q000378:metabolism*; D005315:Fetal Diseases / Q000235:genetics* / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007223:Infant; D008049:Lipase / Q000172:deficiency* / Q000235:genetics*; D008247:Lysosomes / Q000378:metabolism* / Q000648:ultrastructure; D009154:Mutation / Q000235:genetics; D010455:Peptides / Q000235:genetics; D021382:Protein Sorting Signals / Q000235:genetics; D017384:Sequence Deletion / Q000235:genetics; D018411:Spodoptera / Q000235:genetics; D014280:Triglycerides / Q000378:metabolism*; D015223:Wolman Disease / Q000235:genetics* / Q000378:metabolism
chemical_list: D002788:Cholesterol Esters; D010455:Peptides; D021382:Protein Sorting Signals; D014280:Triglycerides; D008049:Lipase