Genetic and biochemical evidence that CESD and Wolman disease are distinguished by residual lysosomal acid lipase activity

Journal Article · Mon Apr 01 04:00:00 EST 1996 · Genomics

DOI:https://doi.org/10.1006/geno.1996.0162· OSTI ID:465927

Aslanidis, C; Ries, S; Fehringer, P ^[1]

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1. Univ. of Regensburg (Germany); and others

Cholesteryl ester storage disease (CESD) and Wolman disease are both autosomal recessive disorders associated with reduced activity and genetic defects of lyso-somal acid lipase (LAL). We provide evidence that the strikingly more severe course of Wolman disease is caused by genetic defects of LAL that leave no residual enzyme activity. In a CESD patient, a G{yields}A mutation at position -1 of the exon 8 in 97% of the LAL hnRNA originating from this allele, while 3% are spliced correctly, resulting in full-length LAL enzyme. The mutant LAL mRNA codes for a protein lacking amino acids 254 to 277. On the other allele, a G{yields}T mutation leads to a premature stop codon at Gly{sub 245}, resulting in inactive LAL enzyme. In addition, the previously identified Leu{sub 179}{yields}pro mutation is present on this allele, and the LAL mRNA is rendered unstable by the premature stop codon. Analysis of two children with Wolman disease showed that both were homozygous for a G{yields}A mutation at position +1 of the same splice donor site as for the CESD patient, leading to skipping of exon 8. In contrast to the CESD patient, no correctly spliced mRNA was detectable. We have also expressed a wildtype LAL cDNA and the mutant LAL cDNA from one Wolman patient in Sf9 and H5 insect cells. We demonstrate that the LAL enzyme generated from the wildtype LAL cDNA was active in homogenates from Sf9 and H5 cells, while the enzyme with the internal deletion of 24 amino acids originating from the LAL cDNA of the Wolman patient was not. 24 refs., 5 figs., 2 tab.

• OSTI ID: 465927
• Journal Information: Genomics, Journal Name: Genomics Journal Issue: 1 Vol. 33; ISSN 0888-7543; ISSN GNMCEP
• Country of Publication: United States
• Language: English

Related Subjects

55 BIOLOGY AND MEDICINE
BASIC STUDIES
AMINO ACIDS
BIOCHEMISTRY
BIOLOGICAL MARKERS
BIOSYNTHESIS
CODONS
DNA SEQUENCING
DNA-CLONING
ELECTROPHORESIS
ENZYME ACTIVITY
GENE MUTATIONS
GENES
GENETICS
HEREDITARY DISEASES
LIPASES
LYSOSOMES
METABOLIC DISEASES
NUCLEOTIDES
PATIENTS
POLYMERASE CHAIN REACTION
RECESSIVE MUTATIONS
SPLICING