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Different missense mutations in histidine‐108 of lysosomal acid lipase cause cholesteryl ester storage disease in unrelated compound heterozygous and hemizygous individuals
Author(s) -
Ries Stefan,
Büchler Christa,
Schindler Gisela,
Aslanidis Charalampos,
Ameis Detlev,
Gasche Christoph,
Jung Nikola,
Schambach Axel,
Fehringer Petra,
Vanier Marie T.,
Belli Dominique C.,
Greten Heiner,
Schmitz Gerd
Publication year - 1998
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/(sici)1098-1004(1998)12:1<44::aid-humu7>3.0.co;2-o
Subject(s) - missense mutation , compound heterozygosity , biology , exon , lysosomal storage disease , mutation , point mutation , lipase , microbiology and biotechnology , inborn error of metabolism , genetics , biochemistry , enzyme , gene
Cholesteryl ester storage disease (CESD) and Wolman disease (WD) are both autosomal recessive disorders associated with reduced activity of lysosomal acid lipase (LAL), that leads to the tissue accumulation of cholesteryl esters in endosomes and lysosomes. WD is caused by genetic defects of LAL that leave no residual enzymatic activity, while in CESD patients a residual LAL activity can be identified. We have analyzed the LAL cDNA in three CESD patients from two nonrelated families and identified the mutations responsible for the disease. The associated genetic defects characterized revealed compound heterozygosity for a splice defect leading to skipping of exon 8, due to a G→A transition at position –1 of the exon 8 splice donor site, and a point mutation leading to a His 108 Pro change (CAT→CCT) in two patients (siblings) with mild CESD phenotype. A further CESD patient was hemizygous for a His 108 →Arg missense mutation (CAT→CGT) in combination with a partial deletion of the LAL gene and was affected more severely. Expression of the LAL enzymes with the His 108 →Pro and His 108 →Arg mutation in insect cells revealed residual enzymatic activities of 4.6% versus 2.7%, respectively, compared with controls. Therefore, His 108 seems to play a crucial role in folding or catalytic activity of the lysosomal acid lipase. This is the first description of two different, naturally occurring mutations involving the same amino acid residue in the lysosomal acid lipase in unrelated CESD patients. Moreover, our results demonstrate that the variable manifestation of CESD can be explained by mutation‐dependent, variable inactivation of the LAL enzyme. Hum Mutat 12:44–51, 1998. © 1998 Wiley‐Liss, Inc.