A histidine to tyrosine replacement in lysosomal acid lipase causes cholesteryl ester storage disease

Franco Pagani, Laura Zagato, Giuliana Merati, Giovanni Paone, Bruno Gridelli, Janette A. Maier

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)1605-1609
Number of pages5
JournalHuman Molecular Genetics
Volume3
Issue number9
Publication statusPublished - Sep 1994

ASJC Scopus subject areas

  • Genetics
  • Statistics, Probability and Uncertainty
  • Applied Mathematics
  • Public Health, Environmental and Occupational Health
  • Molecular Biology
  • Genetics(clinical)

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