Ries, Stefan and Buechler, Christa and Schindler, Gisela and Aslanidis, Charalampos and Ameis, Detlev and Gasche, Christoph and Jung, Nikola and Schambach, Axel and Fehringer, Petra and Vanier, Marie T. and Belli, Dominique C. and Greten, Heiner and Schmitz, Gerd (1998) Different missense mutations in histidine-108 of lysosomal acid lipase cause cholesteryl ester storage disease in unrelated compound heterozygous and hemizygous individuals. HUMAN MUTATION, 12 (1). pp. 44-51. ISSN 1059-7794,
Full text not available from this repository. (Request a copy)Abstract
Cholesteryl ester storage disease (CESD) and Wolman disease (WD) are both autosomal recessive disorders associated with reduced activity of lysosomal acid lipase (LAL), that leads to the tissue accumulation of cholesteryl esters in endosomes and lysosomes. WD is caused by genetic defects of LAL that leave no residual enzymatic activity, while in CESD patients a residual LAL activity can be identified. We have analyzed the LAL cDNA in three CESD patients from two nonrelated families and identified the mutations responsible for the disease. The associated genetic defects characterized revealed compound heterozygosity for a splice defect leading to skipping of exon 8, due to a G-->A transition at position -1 of the exon 8 splice donor site, and a point mutation leading to a His(108)Pro change (CAT-->CCT) in two patients (siblings) with mild CESD phenotype. A further CESD patient was hemizygous for a His(108)-->Arg missense mutation (CAT-->CGT) in combination with a partial deletion of the LAL gene and was affected more severely. Expression of the LAL enzymes with the His(108)-->Pro and His(108)-->Arg mutation in insect cells revealed residual enzymatic activities of 4.6% versus 2.7%, respectively, compared with controls. Therefore, His(108) seems to play a crucial role in folding or catalytic activity of the lysosomal acid lipase. This is the first description of two different, naturally occurring mutations involving the same amino acid residue in the lysosomal acid lipase in unrelated CESD patients. Moreover, our results demonstrate that the variable manifestation of CESD can be explained by mutation-dependent, variable inactivation of the LAL enzyme. (C) 1998 Wiley-Liss, Inc.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | WOLMAN-DISEASE; GENE; ATHEROSCLEROSIS; HYDROLASE; CELLS; Wolman disease; cholesteryl ester storage disease; lysosomal acid lipase; LAL; LIPA; residual activity; mutation |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Klinische Chemie und Laboratoriumsmedizin |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 31 Oct 2023 07:55 |
| Last Modified: | 31 Oct 2023 07:55 |
| URI: | https://pred.uni-regensburg.de/id/eprint/50213 |
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