© 1994 Oxford University Press
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A histidine to tyrosine replacement in lysosomal acid lipase causes cholesteryl ester storage disease
International Centre for Genetic Engineering and Biotechnology Padriciano 99, 1-34013 Trieste 1 Fondazione Rivetti, Laboratory of Biochemistry and Molecular Biology Viale Monte Nero 32, 20135 Milan 2Institute of Experimental Surgery and Transplantation, University of Milan Via F.Sforza 35, 20122 Milan 3Department of Biomedical Sciences and Technology, University of Milan via Olgettina 58, 20100 Milan, Italy
*To whom correspondence should be addressed
Received April 26, 1994; Revised June 23, 1994; Accepted June 23, 1994
The genetic defect causing cholesteryl ester storage disease (CESD) has been investigated in an 11 year old patient. Lysosomal acid lipase (LAL) activity in cultured skin fibroblasts and peripheral lymphocytes was reduced to 
3% and 4% of controls, respectively. The parents had low acid lipase activity in white blood cells. Using the polymerase chain reaction followed by ribonuclease protection assay, we examined the LAL mRNA from the liver of the affected patient to identify small deletion, abnormal splicing or missense mutation. Using this technique we identified a LAL mRNA cytosine to thymidine transition in position 923, predicting a missense substitution of tyrosine for histidine in codon 274. By differential oligonucleotide hybridization on an amplified white blood cell mRNA, the cytosine to thymidine transition was investigated in the family members and in the population. No normal mRNA coding for cytosine in position 923 was detectable in the propositus and mRNA from the phenotypically normal parents coded for both cytosine and thymidine. This can only be accounted for by assuming that the propositus is homozygote for the mutation. The mutation, segregated in the family with levels of acid lipase activity in white blood cells, was not detected in mRNA from 60 normal subjects. These data provide evidence that the cytosine to thymidine transition in position 923 in LAL mRNA causes the clinical expression of CESD in this patient. The predicted substitution of tyrosine for histidine in codon 274 suggests that this amino acid is involved in the structure—function of the lysosomal acid lipase enzyme.
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