title: Identification and functional analysis of genetic variants of the human beta-glucuronidase in a German population sample.
abstract: The deleterious consequences of total beta-glucuronidase deficiency, leading to symptomatic mucopolysaccharidosis type VII (MPS VII), have been firmly established. However, the question of whether sequence variations in beta-glucuronidase of non-MPS VII patients affect expression of the enzyme, thereby explaining the wide inter-individual expression, has not been addressed in a systematic manner. In the present study, a population of 965 subjects were screened for enzyme activity and relevant fractions of the beta-glucuronidase gene were sequenced in those individuals belonging to the highest or lowest decile of activity. The study showed a substantial inter-individual variability of beta-glucuronidase in plasma (range 0.5-150.2 micromol/min) and confirmed the association of beta-glucuronidase activity with gender (P < 0.001), age (r = 0.218; P < 0.001) and body mass index (r = 0.311; P < 0.001). We were able to identify six beta-glucuronidase single base substitutions (-1026A > G, -72G > T, -12G > A, +7728C > T, +14 209C > T and +14 604A > G) in 193 non-MPS VII patients at a rate of one single nucleotide polymorphism (SNP) per 520 bp sequenced. The GG genotype of +14 604A > G and the CT genotype of +14 209C > T were associated with higher beta-glucuronidase activity (P < 0.05). Subsequently, reporter gene assays were carried out to elucidate the effects of the SNPs -1026A > G, -72G > T and -12G > A, and the combined genotype -1026A > G and -12G > A observed in one of the subjects. Variant -12G > A reduced the promoter activity (75%; 95% confidence interval 70-84%, P < 0.05). The present study demonstrates that three of the described SNPs influence the activity and/or expression of beta-glucuronidase. Taken together, the data indicate a rather limited influence of genetic factors on inter-individual variability in beta-glucuronidase activity.
authors.affiliation: Institute of Pharmacology, Peter Holtz Research Center of Pharmacology and Experimental Therapeutics, Ernst Moritz Arndt-University Greifswald, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Gratz
authors.forename: Christiane
authors.initials: C
authors.lastname: Kunert-Keil
authors.forename: Ulrich
authors.initials: U
authors.lastname: John
authors.forename: Ingolf
authors.initials: I
authors.lastname: Cascorbi
authors.forename: Heyo K
authors.initials: HK
authors.lastname: Kroemer
mesh_terms: D003430:Cross-Sectional Studies; D014644:Genetic Variation; D005828:Genetics, Population; D005858:Germany; D005966:Glucuronidase / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D016538:Mucopolysaccharidosis VII / Q000201:enzymology / Q000235:genetics*; D018807:Polymorphism, Single-Stranded Conformational; D044465:White People / Q000235:genetics*
chemical_list: D005966:Glucuronidase