Lysosomal lipase deficiency: Molecular characterization of eleven patients with Wolman or cholesteryl ester storage disease

Tommaso Fasano, Livia Pisciotta, Letizia Bocchi, Ornella Guardamagna, Paola Assandro, Claudio Rabacchi, Paolo Zanoni, Mirella Filocamo, Stefano Bertolini, Sebastiano Calandra

Research output: Contribution to journalArticle

Abstract

Wolman Disease (WD) and cholesteryl ester storage disease (CESD) represent two distinct phenotypes of the same recessive disorder caused by the complete or partial deficiency of lysosomal acidic lipase (LAL), respectively. LAL, encoded by the LIPA gene, hydrolyzes cholesteryl esters derived from cell internalization of plasma lipoproteins. WD is a rapidly progressive and lethal disease characterized by intestinal malabsorption, hepatic and adrenal failure. CESD is characterized by hepatic fibrosis, hyperlipidemia and accelerated atherosclerosis. Aim of the study was the identification of LIPA mutations in three WD and eight CESD patients.The WD patients, all deceased before the first year of age, were homozygous for two novel mutations (c.299+1G>A and c.419G>A) or a mutation (c.796G>T) previously reported as compound heterozygosity in a CESD patient. The two mutations (c.419G>A and c.796G>T) resulting in truncated proteins (p.W140* and p.G266*) and the splicing mutation (c.229+1G>A) were associated with undetectable levels of LIPA mRNA in fibroblasts.All eight CESD patients carried the common mutation c.894G>A known to result not only in a major non-functional transcript with the skipping of exon 8 (p.S275_Q298del), but also in a minor normally spliced transcript producing 5-10% residual LAL activity. The c.894G>A mutation was found in homozygosity in four patients and, as compound heterozygosity, in association with a known (p.H295Y and p.G342R) or a novel (p.W140*) mutation in four other CESD patients. Segregation analysis performed in all patients harboring c.895G>A showed its occurrence on the same haplotype suggesting a common founder ancestor. The other WD and CESD mutations were associated with different haplotypes.

Original languageEnglish
Pages (from-to)450-456
Number of pages7
JournalMolecular Genetics and Metabolism
Volume105
Issue number3
DOIs
Publication statusPublished - Mar 2012

Fingerprint

Cholesterol Ester Storage Disease
Cholesterol Esters
Lipase
Wolman Disease
Mutation
Haplotypes
Intestinal Diseases
Liver Failure
Plasma Cells
Hyperlipidemias
Lipoproteins
Exons
Atherosclerosis
Fibrosis

Keywords

  • Cholesteryl ester storage disease
  • LIPA gene
  • Lysosomal acid lipase
  • Wolman Disease

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics
  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

Lysosomal lipase deficiency : Molecular characterization of eleven patients with Wolman or cholesteryl ester storage disease. / Fasano, Tommaso; Pisciotta, Livia; Bocchi, Letizia; Guardamagna, Ornella; Assandro, Paola; Rabacchi, Claudio; Zanoni, Paolo; Filocamo, Mirella; Bertolini, Stefano; Calandra, Sebastiano.

In: Molecular Genetics and Metabolism, Vol. 105, No. 3, 03.2012, p. 450-456.

Research output: Contribution to journalArticle

Fasano, T, Pisciotta, L, Bocchi, L, Guardamagna, O, Assandro, P, Rabacchi, C, Zanoni, P, Filocamo, M, Bertolini, S & Calandra, S 2012, 'Lysosomal lipase deficiency: Molecular characterization of eleven patients with Wolman or cholesteryl ester storage disease', Molecular Genetics and Metabolism, vol. 105, no. 3, pp. 450-456. https://doi.org/10.1016/j.ymgme.2011.12.008
Fasano, Tommaso ; Pisciotta, Livia ; Bocchi, Letizia ; Guardamagna, Ornella ; Assandro, Paola ; Rabacchi, Claudio ; Zanoni, Paolo ; Filocamo, Mirella ; Bertolini, Stefano ; Calandra, Sebastiano. / Lysosomal lipase deficiency : Molecular characterization of eleven patients with Wolman or cholesteryl ester storage disease. In: Molecular Genetics and Metabolism. 2012 ; Vol. 105, No. 3. pp. 450-456.
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AU - Assandro, Paola

AU - Rabacchi, Claudio

AU - Zanoni, Paolo

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