Acid lipase cross-reacting material in Wolman Disease and cholesterol ester storage disease

The American Journal of Human Genetics (Impact Factor: 10.93). 04/1981; 33(2):203-8.
Source: PubMed


Material cross-reacting with antibodies to acid lipase was demonstrated in fibroblasts of three patients with Wolman disease and three with cholesterol ester storage disease. Quantitation of the immunologically cross-reacting material (CRM) by a single radial immunodiffusion method revealed normal levels in both mutant cell types. CRM specific activity toward triolein and cholesteryl oleate was reduced about 200-fold in the Wolman disease fibroblasts and 50- to 100-fold in the cholesterol ester storage disease cells when compared to normal.

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    • "Homozygous and compound heterozygous mutations of this gene resulting in complete LAL deficiency are the cause of Wolman Disease (WD; OMIM ID: 278000), a rare recessive disorder [9], characterized by massive storage of CE and TG in most tissues, vomiting, diarrhea, anemia, failure to thrive, hepatosplenomegaly and adrenal calcification. Death usually occurs before 1 year of age [5] [10]. Subjects carrying mutations in the LIPA gene which result in residual LAL activity (i.e. "
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    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.
    Full-text · Article · Dec 2011 · Molecular Genetics and Metabolism
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    • "catalyses the hydrolysis of cholesterol esters or triglycerides which have been localized within lysosomes following a receptormediated endocytosis of low-density lipoprotein (LDL) particles (Goldstein et al. 1975; Anderson et al. 1994; Wang et al. 2008). Inborn errors of metabolism for the human gene encoding this enzyme (LIPA) have been described, including Wolman disease (WOD), resulting from a major defect of the gene which leads to a cholesteryl ester storage disease and loss of life, usually within 1 year of age while a second defect of the human LIPA gene generates a milder late-onset cholesteryl ester storage disease (CESD) (Beaudet et al. 1977; Burton and Reed 1981; Hoeg et al. 1984). LIPA is localized on chromosome 10 of the human genome and is highly expressed throughout the body, and contains nine coding exons (Koch et al. 1981; Anderson and Sando 1991; Ameis et al. 1994). "
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    ABSTRACT: Cholesterol ester lipase (LIPA; EC and cholesterol 25-hydroxylase (CH25H; EC play essential role in cholesterol metabolism in the body by hydrolysing cholesteryl esters and triglycerides within lysosomes (LIPA) and catalysing the formation of 25-hydroxycholesterol from cholesterol (CH25H) which acts to repress cholesterol biosynthesis. Bioinformatic methods were used to predict the amino acid sequences, structures and genomic features of several vertebrate LIPA and CH25H genes and proteins, and to examine the phylogeny of vertebrate LIPA. Amino acid sequence alignments and predicted subunit structures enabled the identification of key sequences previously reported for human LIPA and CH25H and transmembrane structures for vertebrate CH25H sequences. Vertebrate LIPA and CH25H genes were located in tandem on all vertebrate genomes examined and showed several predicted transcription factor binding sites and CpG islands located within the 5′ regions of the human genes. Vertebrate LIPA genes contained nine coding exons, while all vertebrate CH25H genes were without introns. Phylogenetic analysis demonstrated the distinct nature of the vertebrate LIPA gene and protein family in comparison with other vertebrate acid lipases and has apparently evolved from an ancestral LIPA gene which predated the appearance of vertebrates. Electronic supplementary material The online version of this article (doi:10.1007/s13205-011-0013-9) contains supplementary material, which is available to authorized users.
    Full-text · Article · Sep 2011
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    • "WD is characterized by early death (usually before age 6 months) and widespread intracellular storage of both CE and TG, mainly in liver, adrenal glands and intestine [1]. In vitro catalytic activity was decreased ~200-fold in WD fibroblasts, but only ~50-fold in CESD fibroblasts [5], showing correlation with the differences in phenotypic severity [6,7]. "
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    ABSTRACT: Cholesterol ester storage disease (CESD) is an autosomal recessive illness that results from mutations in the LIPA gene encoding lysosomal acid lipase. CESD patients present in childhood with hepatomegaly and dyslipidemia characterized by elevated total and low-density lipoprotein cholesterol (LDL-C), with elevated triglycerides and depressed high-density lipoprotein cholesterol (HDL-C). Usual treatment includes a low fat diet and a statin drug. In an 18-year old with CESD, we documented compound heterozygosity for two LIPA mutations: a novel frameshift nonsense mutation and a deletion of exon 8. The patient had been treated with escalating doses of lovastatin for approximately 80 months, with approximately 15% decline in mean LDL-C. The addition of ezetimibe 10 mg to lovastatin 40 mg resulted in an additional approximately 16% decline in mean LDL-C. These preliminary anecdotal findings in a CESD patient with novel LIPA mutations support the longer term safety of statins in an adolescent patient and provide new data about the potential efficacy and tolerability of ezetimibe in this patient group.
    Full-text · Article · Feb 2005 · Lipids in Health and Disease
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