Ries, S. et al. Different missense mutations in histidine-108 of lysosomal acid lipase cause cholesteryl ester storage disease in unrelated compound heterozygous and hemizygous individuals. Hum. Mutat. 12, 44−51

Human Mutation (Impact Factor: 5.14). 01/1998; 12(1):44 - 51. DOI: 10.1002/(SICI)1098-1004(1998)12:1<44::AID-HUMU7>3.0.CO;2-O


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 His108Pro change (CAT→CCT) in two patients (siblings) with mild CESD phenotype. A further CESD patient was hemizygous for a His108→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 His108→Pro and His108→Arg mutation in insect cells revealed residual enzymatic activities of 4.6% versus 2.7%, respectively, compared with controls. Therefore, His108 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.

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    • "Canadian-Norwegian Seedorf et al., 1995 (43) German Ameis et al., 1995 (44) Spanish Muntoni et al., 1995 (8) Sicilian Pagani et al., 1996 (10) Polish-German Aslanidis et al., 1996 (5) Italian, French Redonnet-Vernhet et al., 1997 (33) Austrian Gasche et al., 1997 (38) Brazilian Pagani et al., 1998 (9) Austrian Ries et al., 1998 (37) Brazilian Du et al., 1998 (45) Czech Elleder et al., 2000 (46) NR Anderson et al., 1999 (32) German vom Dahl et al., 1999 (47) Czech Elleder et al., 2000 (46) Irish, Czech Lohse et al., 2000 (34) German Rassoul et al., 2001 (48) German Drebber et al., 2005 (49) NR Tadiboyina et al., 2005 (50) Australian Hooper et al., 2008 (36) Italian Pisciotta et al., 2009 (41) Italian, Greek, Croatian Fasano et al., 2012 (39) "
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    ABSTRACT: Unlabelled: Cholesteryl ester storage disease (CESD) and Wolman disease are autosomal recessive later-onset and severe infantile disorders, respectively, which result from the deficient activity of lysosomal acid lipase (LAL). LAL is encoded by LIPA (10q23.31) and the most common mutation associated with CESD is an exon 8 splice junction mutation (c.894G>A; E8SJM), which expresses only ∼3%-5% of normally spliced LAL. However, the frequency of c.894G>A is unknown in most populations. To estimate the prevalence of CESD in different populations, the frequencies of the c.894G>A mutation were determined in 10,000 LIPA alleles from healthy African-American, Asian, Caucasian, Hispanic, and Ashkenazi Jewish individuals from the greater New York metropolitan area and 6,578 LIPA alleles from African-American, Caucasian, and Hispanic subjects enrolled in the Dallas Heart Study. The combined c.894G>A allele frequencies from the two cohorts ranged from 0.0005 (Asian) to 0.0017 (Caucasian and Hispanic), which translated to carrier frequencies of 1 in 1,000 to ∼1 in 300, respectively. No African-American heterozygotes were detected. Additionally, by surveying the available literature, c.894G>A was estimated to account for 60% (95% confidence interval [CI]: 51%-69%) of reported mutations among multiethnic CESD patients. Using this estimate, the predicted prevalence of CESD in the Caucasian and Hispanic populations is ∼0.8 per 100,000 (∼1 in 130,000; 95% CI: ∼1 in 90,000 to 1 in 170,000). Conclusion: These data indicate that CESD may be underdiagnosed in the general Caucasian and Hispanic populations, which is important since clinical trials of enzyme replacement therapy for LAL deficiency are currently being developed. Moreover, future studies on CESD prevalence in African and Asian populations may require full-gene LIPA sequencing to determine heterozygote frequencies, since c.894G>A is not common in these racial groups.
    Hepatology 09/2013; 58(3). DOI:10.1002/hep.26327 · 11.06 Impact Factor
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    ABSTRACT: Multiparameter flow cytometry reveals a complex heterogeneity of mononuclear phagocyte differentiation within the peripheral blood compartment. In this study, the relation of abnormal cellular lipid metabolism to the phenotype of peripheral blood mononuclear phagocytes, which finally may be related to atherogenesis, was analyzed using recently characterized autosomal recessive defects of lysosomal acid lipase (LAL) expression as model system. The reduction of LAL activity in nine heterozygote, disease free carriers of mutations from two cholesteryl ester storage disease (CESD) pedigrees and the family of a patient with Wolman disease was associated with an increased fraction of monocytes which expressed CD56 (N-CAM) (4.1 +/- 2.7% of monocytes, compared to 2.2 +/- 0.5% in ten controls, P < 0.05), an antigen characteristic of immature myeloid cells, suggesting an increased turnover of monocytes. Furthermore, a trend was observed towards an enhanced blood pool of more mature mononuclear phagocytes which show decreased expression of the 55 kD lipopolysaccharide receptor (CD14) together with either expression of the Fc-gamma-receptor III (CD16) or a high expression of CD33. A similar phenotype of peripheral mononuclear phagocytes was observed in the two CESD patients analyzed. In conclusion, our data suggest that these monogenetic defects of lysosomal lipoprotein metabolism are associated with complex alterations of mononuclear phagocyte differentiation and extravasation.
    Atherosclerosis 04/1997; 130(1-2):215-21. DOI:10.1016/S0021-9150(97)06065-6 · 3.99 Impact Factor
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