title: A novel variant of lysosomal acid lipase (Leu336-->Pro) associated with acid lipase deficiency and cholesterol ester storage disease.
abstract: Cholesterol ester storage disease (CESD) is associated with premature atherosclerosis, hepatomegaly, elevated LDL cholesterol levels, and in most cases, low HDL cholesterol levels. Previous studies have shown a G-->A mutation at the 3' splice junction of exon 8 (E8SJM) of the gene encoding lysosomal acid lipase (LAL) in two kindreds with CESD. In a Canadian-Norwegian kindred with this disease, we show this mutation in conjunction with an as yet unknown T-->C transition in exon 10 predicting a Leu336-->Pro (L336P) replacement and an A-->C transversion in exon 2 predicting a T-6P replacement in the prepeptide. Identification of the L336P rather than the T-6P replacement as the second defect underlying CESD in our patient is deduced from three lines of evidence. First, the E8SJM allele is located in cis with the mutation predicting the T-6P-encoding allele but in trans with the L336P-encoding allele; second, the L336P but not the T-6P replacement cosegregates with low LAL activity in the family; third, the T-6P replacement was found in 6 of 28 alleles from subjects with normal lysosomal acid lipase activity, suggesting that this variant represents a frequent nonfunctional polymorphism. Since the residual LAL activity is higher and the clinical phenotype based on plasma lipid values and severity of hepatosplenomegaly is milder in this case than in a previously studied case who was homozygous for the E8SJM allele, we conclude that the L336P variant appears to be associated with a phenotypically mild form of CESD.
authors.affiliation: Institut für Arterioskleroseforschung, Westfälische Wilhelms-Universität, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Seedorf
authors.forename: H
authors.initials: H
authors.lastname: Wiebusch
authors.forename: S
authors.initials: S
authors.lastname: Muntoni
authors.forename: N C
authors.initials: NC
authors.lastname: Christensen
authors.forename: F
authors.initials: F
authors.lastname: Skovby
authors.forename: V
authors.initials: V
authors.lastname: Nickel
authors.forename: M
authors.initials: M
authors.lastname: Roskos
authors.forename: H
authors.initials: H
authors.lastname: Funke
authors.forename: L
authors.initials: L
authors.lastname: Ose
authors.forename: G
authors.initials: G
authors.lastname: Assmann
mesh_terms: D000328:Adult; D000483:Alleles; D000595:Amino Acid Sequence; D001483:Base Sequence; D002784:Cholesterol / Q000097:blood; D015217:Cholesterol Ester Storage Disease / Q000201:enzymology* / Q000235:genetics; D008076:Cholesterol, HDL / Q000097:blood; D005091:Exons; D005260:Female; D006579:Heterozygote; D006801:Humans; D008049:Lipase / Q000097:blood / Q000172:deficiency / Q000235:genetics*; D008214:Lymphocytes / Q000201:enzymology; D008247:Lysosomes / Q000201:enzymology*; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D017422:Sequence Analysis, DNA; D014280:Triglycerides / Q000097:blood; D001616:beta-Galactosidase / Q000097:blood
chemical_list: D008076:Cholesterol, HDL; D014280:Triglycerides; D002784:Cholesterol; D008049:Lipase; D001616:beta-Galactosidase