Mutations at the lysosomal acid cholesteryl ester hydrolase gene locus in Wolman disease.

Abstract

The genomic sequences encoding the human lysosomal acid lipase/cholesteryl esterase (sterol esterase; EC 3.1.1.13) have been isolated and sequenced, and the information has been used to identify mutations in both alleles of the gene from a patient with Wolman disease, an autosomal recessive lysosomal lipid storage disorder. The genomic locus consists of 10 exons spread over 36 kb. The 5' flanking region is G+C-rlch and has caracteristics of a "housekeeping" gene promoter. One ofthe identified mutations involves the insertion of a T residue after POsi 634, resulting in the appearance of an in-frame translation stop signal 13 codons downstream. The second mutation is a T-to-C transition at nucleotide 638. This results in a leucine-to-proline substitution at amino acid 179 and is predicted to lead to the disruption of the a-helical structure in a highly conserved region of the protein.

Early steps in steroidogenesis: intracellular cholesterol trafficking

“…Mutations in the LIPA gene cause Wolman disease and its milder variant, cholesterol ester storage disease (83)(84)(85)(86)(87)(88). Wolman disease is characterized by accumulated cholesteryl the extracellular adaptor protein MD-2, which is similar to that present in various lipid-binding proteins ( 111 ).…”

Wolman's Disease: The King Faisal Specialist Hospital and Research Centre Experience

“…7 It contains 10 exons dispersed over 45 kilobases. 8 Several mutations have been identified, some of which lead to almost complete loss of enzyme activity and to the phenotype of Wolman's disease, 9 while other mutations cause only partial disruption of the enzyme action, leading to a clinically more benign disease, the so-called cholesterol ester storage disease. A leucine substitution for proline at Codon position 357, for example, leads to such a mild phenotype.…”

Distinct Endosomal Compartments in Early Trafficking of Low Density Lipoprotein-derived Cholesterol

“…In contrast, when the cells were chased for a longer time period (for 1 h) in the absence of CD, a significant difference in the [ 3 H]cholesterol distribution was seen between 25RA and CT43 cells (Fig. 3C, solid bars 3 H counts recovered from different samples, the values reported were normalized so that the sum of counts in cellular cholesterol and CL was the same for different samples. C, after the pulse, 25RA and CT43 cells were chased at 37°C in the presence or absence of CD for 1 h. [ 3 H]Cholesterol in each Percoll fraction and in the medium was counted.…”