Human Molecular Genetics, Vol 5, 1611-1617, Copyright © 1996 by Oxford University Press
F Pagani, R Garcia, R Pariyarath, C Stuani, B Gridelli, G Paone and FE Baralle
Lysosomal acid lipase (LAL) gene mutations were identified in three
patients with cholesteryl ester storage disease (CESD). Direct sequencing
of genomic DNA revealed that: patient 1 was a compound heterozygote for a
P181L mutation and an A to G3' splice site substitution that causes
skipping of exon 7, with a loss of 49 amino acids from LAL (delta 205-253);
patient 2 was a compound heterozygote for a G66V mutation and a 5' splice
site mutation (G to A) that leads to skipping of exon 8 (delta 254-277);
and patient 3 was a compound heterozygote for a L273S mutation and an
unidentified null allele. Furthermore, patients 2 and 3 showed a novel G-2A
polymorphism that could be detected by an Xbal restriction fragment length
polymorphism. All these mutants and a previously reported H274Y allele were
expressed in vitro in HeLa cells using the vaccinia T7 expression system.
The resulting recombinant proteins were inactive towards cholesteryl oleate
and trioleylglycerol, demonstrating the direct involvement of these
mutations in the pathogenesis of CESD. Immunoblotting of normal LAL
expressed in HeLa cells revealed four major molecular forms, at least two
of high molecular mass (54 and 50-51 kDa) and two of low molecular mass (42
and 43 kDa). L273S and P181L substitutions and delta 254-277 were shown to
result in altered LAL molecular forms, some of which suggest that
post-translational processing may interfere with the catalytic activity of
LAL.
ARTICLES
Expression of lysosomal acid lipase mutants detected in three patients with cholesteryl ester storage disease
International Centre for Genetic Engineering and Biotechnology, Trieste, Italy.
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