New lysosomal acid lipase gene mutants explain the phenotype of Wolman disease and cholesteryl ester storage disease

Franco Pagani, Rajalakshmi Pariyarath, Rodolfo Garcia, Cristiana Stuani, Alberto B. Burlina, Giacomo Ruotolo, Marco Rabusin, Francisco E. Baralle

Research output: Contribution to journalArticlepeer-review


Deficiency of lysosomal acid lipase (LAL) leads to either Wolman disease (WD) or the more benign cholesteryl ester storage disease (CESD). To identify the molecular basis of the different phenotypes we have characterised the LAL gene mutations in three new patients with LAL deficiency. A patient with WD was homozygote for a null allele Y303X. The other two patients, with CESD, presented either homozygosity for T267I or compound heterozygosity consisting of Q64R and an exon 8 donor splice site substitution (G∅ in position -1). The mutants T267I and Q64R and the previously reported L273S, G66V, and H274Y CESD substitutions, overexpressed in stable clones, were found to be fully glycosylated and show an enzymatic activity of 3-8% of that of normal LAL. On the other hand, the Δ254-277 mutant protein derived from exon 8 skipping and the Y303X protein were totally inactive. By transient transfection of hybrid minigene constructs, the CESD G→A (-1) substitution resulted in partial exon inclusion, thus allowing the production of a small amount of normal LAL mRNA and hence of a functional enzyme. In contrast, a G→A substitution observed in WD at position + 1 of the same exon 8 donor site resulted in complete exon skipping and the sole production of an inactive Δ254-277 protein. In conclusion, LAL genotypes determine the level of residual enzymatic activity, thus explaining the severity of the phenotype.

Original languageEnglish
Pages (from-to)1382-1388
Number of pages7
JournalJournal of Lipid Research
Issue number7
Publication statusPublished - Jul 1998


  • Alternative splicing
  • Mutation
  • Phenotype
  • Recombinant proteins
  • Wolman disease/etiology

ASJC Scopus subject areas

  • Endocrinology


Dive into the research topics of 'New lysosomal acid lipase gene mutants explain the phenotype of Wolman disease and cholesteryl ester storage disease'. Together they form a unique fingerprint.

Cite this