Cholesteryl Ester Storage Disease (CESD) due to novel mutations in the LIPA gene
Introduction
Lysosomal acid lipase (LAL)1 (GenBank a.n. CAA83495) is a lysosomal enzyme which hydrolyzes cholesteryl esters (CE) and triglycerides (TG) internalized via receptor-mediated endocytosis of plasma lipoprotein particles [1], [2], [3], [4], [5], [6]. The LAL-mediated release of free cholesterol (FC) within the cell causes down-regulation of HMG-CoA reductase (HMGR) and LDL receptor (LDLR) genes and up-regulation of cholesterol esterification by the activation of ACAT enzyme [1], [5].
In humans LAL is encoded by the LIPA gene (GenBank a.n. NG008194) located on chromosome 10 (10q23.2-q23.3) [7], [8]. Homozygous and compound heterozygous mutations of this gene resulting in complete LAL deficiency are the cause of Wolman’s disease (OMIM +278000), a rare recessive disorder [9], characterized by massive storage of CE and TG in most tissues, failure to thrive and death, usually before one year of age [5], [10]. Subjects carrying mutations in the LIPA gene which result in residual LAL activity (i.e. 2–8% of controls in blood leukocytes) develop the less severe disorder known as Cholesteryl Ester Storage Disease (CESD) [5], [11], [12], [13]. CESD may be diagnosed in childhood or late in life, as its phenotypic expression shows a broad spectrum of severity of clinical manifestations [5], [12], [13]. The frequency of CESD in the population is presently unknown. A population survey of the heterozygous carriers of the most frequent LIPA gene mutation (c.894 G>A in exon 8) found in CESD patients suggests that the prevalence of CESD may be around 2.5/100,000 [14].
In the present work we report the molecular characterization of three patients with CESD, who were found to be compound heterozygous, carrying the common LIPA gene mutation (c.894 G>A, del p.S275_Q298), in combination with two novel mutations resulting in null alleles.
Section snippets
Family 1
The probands (subjects III.2 and III.3) (Fig. 1) were biovular twin sisters, in whom the clinical diagnosis of CESD was made at 9 years of age, when one of them was admitted to a paediatric hospital for mononucleosis infection. The first clue to the diagnosis was the finding of a persistent elevation of plasma liver enzymes and the presence of an otherwise unexplained hepatomegaly which required liver biopsy. The results of liver biopsy (see below) and of the assay of LAL activity in peripheral
Plasma lipids
Table 1 shows the pre-treatment plasma lipid levels in the two probands (III.2 and III.3) and their relatives. The affected sisters were found to have a marked elevation of TC, TG and ApoB, associated with a moderate reduction of HDL-C and apoA-I.
Liver biopsy
The liver biopsy was performed only in proband III.3 when she was 9 years old. Light-microscopy and immunohistochemistry showed massive vesicular steatosis, portal and septal fibrosis, portal infiltration of macrophages (CD68-positive) and lymphoid
Discussion
In this paper we describe three patients, from two families, affected by CESD. In the twin sisters of Family 1 the clinical diagnosis was made in the first decade of life, following the fortuitous observation of a persistent elevation of serum liver enzymes in apparently healthy children, which prompted the paediatrician to perform liver biopsy, followed by LAL activity assay in peripheral blood leukocytes. In striking contrast, the diagnosis of CESD in the proband of Family 2 was made late in
Acknowledgments
This work was supported by grants from the University of Genova (S.B.) and University of Modena and Reggio Emilia (S.C.).
References (31)
- et al.
Role of lysosomal acid lipase in the metabolism of plasma low density lipoprotein. Observations in cultured fibroblasts from a patient with cholesteryl ester storage disease
J. Biol. Chem.
(1975) - et al.
Recognition and receptor-mediated endocytosis of the lysosomal acid lipase secreted by cultured human fibroblasts
J. Lipid Res.
(1982) - et al.
Characterization of lysosomal acid lipase by site-directed mutagenesis and heterologous expression
J. Biol. Chem.
(1995) - et al.
Cloning and expression of cDNA encoding human lysosomal acid lipase/cholesteryl ester hydrolase. Similarities to gastric and lingual lipases
J. Biol. Chem.
(1991) - et al.
In situ localization of the genetic locus encoding the lysosomal acid lipase/cholesteryl esterase (LIPA) deficient in Wolman disease to chromosome 10q23.2-q23.3
Genomics
(1993) - et al.
Genomic organization of the human lysosomal acid lipase gene (LIPA)
Genomics
(1994) - et al.
Genetic and biochemical evidence that CESD and Wolman disease are distinguished by residual lysosomal acid lipase activity
Genomics
(1996) - et al.
Compound heterozygosity for a Wolman mutation is frequent among patients with cholesteryl ester storage disease
J. Lipid Res.
(2000) - et al.
Additive effect of mutations in LDLR and PCSK9 genes on the phenotype of familial hypercholesterolemia
Atherosclerosis
(2006) - et al.
Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI
J. Lipid Res.
(1990)
New lysosomal acid lipase gene mutants explain the phenotype of Wolman disease and cholesteryl ester storage disease
J. Lipid Res.
A 5’ splice-site mutation and a dinucleotide deletion in the lysosomal acid lipase gene in two patients with cholesteryl ester storage disease
J. Lipid Res.
Molecular and enzymatic analyses of lysosomal acid lipase in cholesteryl ester storage disease
Mol. Genet. Metab.
Lysosomal acid lipase mutations that determine phenotype in Wolman and Cholesteryl Ester Storage Disease
Mol. Genet. Metab.
A novel mutation of apolipoprotein A-I gene in a family with familial combined hyperlipidemia
Atherosclerosis
Cited by (66)
Recent insights into lysosomal acid lipase deficiency
2023, Trends in Molecular MedicineLysosomal acid lipase: Roles in rare deficiency diseases, myeloid cell biology, innate immunity, and common neutral lipid diseases
2022, Cholesterol: From Chemistry and Biophysics to the ClinicLysosomal acid lipase deficiency in pediatric patients: a scoping review
2022, Jornal de PediatriaLysosomal Storage Disorders
2020, Emery and Rimoin’s Principles and Practice of Medical Genetics and Genomics: Metabolic DisordersThe Adrenal Cortex and Its Disorders
2020, Sperling Pediatric Endocrinology: Expert Consult - Online and PrintGenetic Causes of Liver Disease: When to Suspect a Genetic Etiology, Initial Lab Testing, and the Basics of Management
2019, Medical Clinics of North America