Compound heterozygosity for a Wolman mutation is frequent among patients with cholesteryl ester storage disease

Citation
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
Citations number
33
Categorie Soggetti
Biochemistry & Biophysics
Journal title
JOURNAL OF LIPID RESEARCH
ISSN journal
00222275 → ACNP
Volume
41
Issue
1
Year of publication
2000
Pages
23 - 31
Database
ISI
SICI code
0022-2275(200001)41:1<23:CHFAWM>2.0.ZU;2-F
Abstract
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.