[BGLR_HUMAN] Defects in GUSB are the cause of mucopolysaccharidosis type 7 (MPS7) [MIM:253220]; also known as Sly syndrome. MPS7 is an autosomal recessive lysosomal storage disease characterized by inability to degrade glucuronic acid-containing glycosaminoglycans. The phenotype is highly variable, ranging from severe lethal hydrops fetalis to mild forms with survival into adulthood. Most patients with the intermediate phenotype show hepatomegaly, skeletal anomalies, coarse facies, and variable degrees of mental impairment. Note=Mucopolysaccharidosis type 7 is associated with non-immune hydrops fetalis, a generalized edema of the fetus with fluid accumulation in the body cavities due to non-immune causes. Non-immune hydrops fetalis is not a diagnosis in itself but a symptom, a feature of many genetic disorders, and the end-stage of a wide variety of disorders.
[BGLR_HUMAN] Plays an important role in the degradation of dermatan and keratan sulfates.
The X-ray structure of the homotetrameric lysosomal acid hydrolase, human beta-glucuronidase (332,000 Mr), has been determined at 2.6 A resolution. The tetramer has approximate dihedral symmetry and each promoter consists of three structural domains with topologies similar to a jelly roll barrel, an immunoglobulin constant domain and a TIM barrel respectively. Residues 179-204 form a beta-hairpin motif similar to the putative lysosomal targeting motif of cathepsin D, supporting the view that lysosomal targeting has a structural basis. The active site of the enzyme is formed from a large cleft at the interface of two monomers. Residues Glu 451 and Glu 540 are proposed to be important for catalysis. The structure establishes a framework for understanding mutations that lead to the human genetic disease mucopolysaccharidosis VII, and for using the enzyme in anti-cancer therapy.
Structure of human beta-glucuronidase reveals candidate lysosomal targeting and active-site motifs.,Jain S, Drendel WB, Chen ZW, Mathews FS, Sly WS, Grubb JH Nat Struct Biol. 1996 Apr;3(4):375-81. PMID:8599764
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
↑ Vervoort R, Lissens W, Liebaers I. Molecular analysis of a patient with hydrops fetalis caused by beta-glucuronidase deficiency, and evidence for additional pseudogenes. Hum Mutat. 1993;2(6):443-5. PMID:8111412 doi:http://dx.doi.org/10.1002/humu.1380020604
↑ Tomatsu S, Fukuda S, Sukegawa K, Ikedo Y, Yamada S, Yamada Y, Sasaki T, Okamoto H, Kuwahara T, Yamaguchi S, et al.. Mucopolysaccharidosis type VII: characterization of mutations and molecular heterogeneity. Am J Hum Genet. 1991 Jan;48(1):89-96. PMID:1702266
↑ Shipley JM, Klinkenberg M, Wu BM, Bachinsky DR, Grubb JH, Sly WS. Mutational analysis of a patient with mucopolysaccharidosis type VII, and identification of pseudogenes. Am J Hum Genet. 1993 Mar;52(3):517-26. PMID:7680524
↑ Wu BM, Tomatsu S, Fukuda S, Sukegawa K, Orii T, Sly WS. Overexpression rescues the mutant phenotype of L176F mutation causing beta-glucuronidase deficiency mucopolysaccharidosis in two Mennonite siblings. J Biol Chem. 1994 Sep 23;269(38):23681-8. PMID:8089138
↑ Vervoort R, Islam MR, Sly W, Chabas A, Wevers R, de Jong J, Liebaers I, Lissens W. A pseudodeficiency allele (D152N) of the human beta-glucuronidase gene. Am J Hum Genet. 1995 Oct;57(4):798-804. PMID:7573038
↑ Yamada S, Tomatsu S, Sly WS, Islam R, Wenger DA, Fukuda S, Sukegawa K, Orii T. Four novel mutations in mucopolysaccharidosis type VII including a unique base substitution in exon 10 of the beta-glucuronidase gene that creates a novel 5'-splice site. Hum Mol Genet. 1995 Apr;4(4):651-5. PMID:7633414
↑ Vervoort R, Islam MR, Sly WS, Zabot MT, Kleijer WJ, Chabas A, Fensom A, Young EP, Liebaers I, Lissens W. Molecular analysis of patients with beta-glucuronidase deficiency presenting as hydrops fetalis or as early mucopolysaccharidosis VII. Am J Hum Genet. 1996 Mar;58(3):457-71. PMID:8644704
↑ Islam MR, Vervoort R, Lissens W, Hoo JJ, Valentino LA, Sly WS. beta-Glucuronidase P408S, P415L mutations: evidence that both mutations combine to produce an MPS VII allele in certain Mexican patients. Hum Genet. 1996 Sep;98(3):281-4. PMID:8707294
↑ Vervoort R, Buist NR, Kleijer WJ, Wevers R, Fryns JP, Liebaers I, Lissens W. Molecular analysis of the beta-glucuronidase gene: novel mutations in mucopolysaccharidosis type VII and heterogeneity of the polyadenylation region. Hum Genet. 1997 Apr;99(4):462-8. PMID:9099834
↑ Vervoort R, Gitzelmann R, Bosshard N, Maire I, Liebaers I, Lissens W. Low beta-glucuronidase enzyme activity and mutations in the human beta-glucuronidase gene in mild mucopolysaccharidosis type VII, pseudodeficiency and a heterozygote. Hum Genet. 1998 Jan;102(1):69-78. PMID:9490302
↑ Schwartz I, Silva LR, Leistner S, Todeschini LA, Burin MG, Pina-Neto JM, Islam RM, Shah GN, Sly WS, Giugliani R. Mucopolysaccharidosis VII: clinical, biochemical and molecular investigation of a Brazilian family. Clin Genet. 2003 Aug;64(2):172-5. PMID:12859417
↑ Storch S, Wittenstein B, Islam R, Ullrich K, Sly WS, Braulke T. Mutational analysis in longest known survivor of mucopolysaccharidosis type VII. Hum Genet. 2003 Feb;112(2):190-4. Epub 2002 Nov 5. PMID:12522561 doi:10.1007/s00439-002-0849-5
↑ Jain S, Drendel WB, Chen ZW, Mathews FS, Sly WS, Grubb JH. Structure of human beta-glucuronidase reveals candidate lysosomal targeting and active-site motifs. Nat Struct Biol. 1996 Apr;3(4):375-81. PMID:8599764