© 1995 American Heart Association, Inc.
Articles |
A Novel Variant of Lysosomal Acid Lipase (Leu336
Pro) Associated With Acid Lipase Deficiency and Cholesterol Ester Storage Disease
From the Institut für Arterioskleroseforschung (U.S., H.W., S.M., V.N., M.R., H.F., G.A.) and the Institut für Klinische Chemie und Laboratoriumsmedizin (S.M., H.F., G.A.), Zentrallaboratorium, Westfälische Wilhelms-Universität, Germany; the Department of Pediatrics (N.C.C.), Sønderborg Sygehus, Sønderborg, Denmark; the Department of Pediatrics (F.S.), Rigshospitalet, Copenhagen, Denmark; and the Lipid Clinic (L.O.), Rikshospitalet, Oslo, Norway.
Correspondence to Udo Seedorf, Institut für Arterioskleroseforschung an der Universität Münster, Domagkstr 3 48149 Münster, FRG.
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
TC transition in exon 10 predicting a Leu336Pro
(L336P) replacement and an AC 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.
Key Words: lysosomal storage diseases • genetics • cholesterol • atherosclerosis • liver diseases
This article has been cited by other articles:
 |
|
 |
|
  S. Muntoni, H. Wiebusch, M. Jansen-Rust, S. Rust, U. Seedorf, H. Schulte, K. Berger, H. Funke, and G. Assmann Prevalence of Cholesteryl Ester Storage Disease Arterioscler. Thromb. Vasc. Biol., August 1, 2007; 27(8): 1866 - 1868. [Full Text] [PDF]
|
|
|
|
 |
|
 P. Lohse, S. Maas, P. Lohse, M. Elleder, J. M. Kirk, G. T. N. Besley, and D. Seidel Compound heterozygosity for a Wolman mutation is frequent among patients with cholesteryl ester storage disease J. Lipid Res., January 1, 2000; 41(1): 23 - 31. [Abstract] [Full Text]
|
|
|
|
 |
|
 A. Roussel, S. Canaan, M.-P. Egloff, M. Riviere, L. Dupuis, R. Verger, and C. Cambillau Crystal Structure of Human Gastric Lipase and Model of Lysosomal Acid Lipase, Two Lipolytic Enzymes of Medical Interest J. Biol. Chem., June 11, 1999; 274(24): 16995 - 17002. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Lohse, S. Maas, P. Lohse, A. C. Sewell, O. P. van Diggelen, and D. Seidel Molecular defects underlying Wolman disease appear to be more heterogeneous than those resulting in cholesteryl ester storage disease J. Lipid Res., February 1, 1999; 40(2): 221 - 228. [Abstract] [Full Text]
|
|
|
|
|
|
F. Pagani, R. Pariyarath, R. Garcia, C. Stuani, A. B. Burlina, G. Ruotolo, M. Rabusin, and F. E. Baralle New lysosomal acid lipase gene mutants explain the phenotype of Wolman disease and cholesteryl ester storage disease J. Lipid Res., July 1, 1998; 39(7): 1382 - 1388. [Abstract] [Full Text]
|
|