P. Lohse et al., Compound heterozygosity for a Wolman mutation is frequent among patients with cholesteryl ester storage disease, J LIPID RES, 41(1), 2000, pp. 23-31
Cholesteryl ester storage disease and Wolman disease are rare autosomal rec
essive Lipoprotein-processing disorders caused by mutations in the gene enc
oding human lysosomal acid lipase. Thus far we have elucidated the genetic
defects in 15 unrelated CESD patients. Seven were homozygotes for the preva
lent hLAL exon 8 splice junction mutation which results in incomplete exon
skipping, while eight probands were compound heterozygotes for E8SJM and a
rare mutation on the second chromosome, In this report, we describe the mol
ecular basis of CESD in three compound heterozygous subjects of Czech and I
rish origin, RFLP and DNA sequence analysis revealed that they were heteroa
llelic for the common G(934)-->A substitution in exon 8 of the hLAL gene an
d a mutation which, if inherited on both alleles, would be expected to resu
lt in complete loss of enzyme activity and to cause Wolman disease, In pati
ents A, M. and J, J., two nucleotide deletions in exons 7 and 10 were detec
ted, involving a T at position 722, 723, or 724 and a G in a stretch of fiv
e guanosines at positions 1064-1068 of the hLAL cDNA. Both mutations result
in premature termination of protein translation at residues 219 and 336, r
espectively, and in the production of truncated, inactive enzymes. Subject
D. H., in contrast, is a compound heterozygote for the Arg(44)-->Stop mutat
ion previously described in a French CESD proband, Combined with data in th
e literature, our results demonstrate that compound heterozygosity for a mu
tation causing Wolman disease is common among cholesteryl ester storage dis
ease patients.