J. Lipid Res.  Neurobiology of Lipids (ISSN1683-5506)
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Journal of Lipid Research, Vol. 41, 23-31, January 2000
Copyright © 2000 by Lipid Research, Inc.


Original Article

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

Peter Lohsea, Sylke Maasa, Pia Lohsea, Milan Ellederb, Jean M. Kirkc, Guy T. N. Besleyd, and Dietrich Seidela
a Department of Clinical Chemistry, Grosshadern Clinic, University of Munich, Munich, Germany
b Institute of Inherited Metabolic Disorders, Charles University Prague, 1st Faculty of Medicine and General Faculty Hospital, Prague, Czech Republic
c Department of Paediatric Biochemistry, Edinburgh Sick Children's NHS Trust, Royal Hospital for Sick Children, Edinburgh, Great Britain
d Willink Biochemical Genetics Unit, Manchester Royal Children's Hospital, Manchester, Great Britain

Correspondence to: Peter Lohse

Cholesteryl ester storage disease and Wolman disease are rare autosomal recessive lipoprotein-processing disorders caused by mutations in the gene encoding human lysosomal acid lipase. Thus far we have elucidated the genetic defects in 15 unrelated CESD patients. Seven were homozygotes for the prevalent 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 molecular basis of CESD in three compound heterozygous subjects of Czech and Irish origin. RFLP and DNA sequence analysis revealed that they were heteroallelic for the common G934->A substitution in exon 8 of the hLAL gene and a mutation which, if inherited on both alleles, would be expected to result in complete loss of enzyme activity and to cause Wolman disease. In patients A. M. and J. J., two nucleotide deletions in exons 7 and 10 were detected, involving a T at position 722, 723, or 724 and a G in a stretch of five guanosines at positions 1064;–1068 of the hLAL cDNA. Both mutations result in premature termination of protein translation at residues 219 and 336, respectively, and in the production of truncated, inactive enzymes. Subject D. H., in contrast, is a compound heterozygote for the Arg44->Stop mutation previously described in a French CESD proband.

Combined with data in the literature, our results demonstrate that compound heterozygosity for a mutation causing Wolman disease is common among cholesteryl ester storage disease patients.—Lohse, P., 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. 2000. 41: 23;–31.

Supplementary key words: lipid metabolism, lysosomal storage disease, enzyme deficiency, genotype, point mutation


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