Mutations and polymorphisms in GUSB gene in mucopolysaccharidosis VII (Sly Syndrome)

Abstract

Mucopolysaccharidosis VII (MPS VII; Sly syndrome) is an autosomal recessive disorder caused by a deficiency of b-glucuronidase (GUS, EC 3.2.1.31; GUSB). GUS is required to degrade glycosaminoglycans (GAGs), including heparan sulfate (HS), dermatan sulfate (DS), and chondroitin-4,6-sulfate (CS). Accumulation of undegraded GAGs in lysosomes of affected tissues leads to mental retardation, short stature, hepatosplenomegaly, bone dysplasia, and hydrops fetalis. We summarize information on the 49 unique, disease-causing mutations determined so far in the GUS gene, including nine novel mutations (eight missense and one splice-site). This heterogeneity in GUS gene mutations contributes to the extensive clinical variability among patients with MPS VII. One pseudodeficiency allele, one polymorphism causing an amino acid change, and one silent variant in the coding region are also described. Among the 103 analyzed mutant alleles, missense mutations accounted for 78.6%; nonsense mutations, 12.6%; deletions, 5.8%; and splice-site mutations, 2.9%. Transitional mutations at CpG dinucleotides made up 40.8% of all the described mutations. The five most frequent mutations (accounting for 44/103 alleles) were exonic point mutations, p.L176F, p.R357X, p.P408S, p.P415L, and p.A619 V. Genotype/phenotype correlation was attempted by correlating the effects of certain missense mutations or enzyme activity and stability within phenotypes. These were in turn correlated with the location of the mutation in the tertiary structure of GUS. A total of seven murine, one feline, and one canine model of MPS VII have been characterized for phenotype and genotype.

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“…Human Gusb is known to be polymorphic, with over 750 SNPs recorded in the dbSNP database. Forty-nine mutations causing overt disease have been identified in MPSVII patient populations (32), while the prevalence and impact, if any, of other variants remain undefined. Human GUSB enzymatic activity levels in the general population have been shown to exhibit a wide distribution and vary in tissue and serum samples by up to 30-fold (38, 39), differences larger than those observed between high-expressing (B6, CBA/Ca) and low-expressing (C3H, CBA/J) inbred mouse strains used in this study ( Figure 1D and ref.…”

“…GUSB is a lysosomal hydrolase that catalyzes an essential step in the homeostatic degradation of glycosaminoglycans (GAGs). Severe autosomal recessive GUSB deficiency causes a lysosomal storage disease known as MPSVII, one characteristic of which is spontaneous accumulation of partially degraded GAGs within lysosomes (32). C3H mice begin to develop mild lysosomal accumulation of GAGs by 12 months of age, but younger 9-to 11-week-old mice appear to be unaffected (33).…”

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“…So far, 49 unique disease-causing mutations were determined in the GUS gene, including nine novel mutations (eight missense and one splice-site). This heterogeneity in GUS gene mutations contributes to the extensive clinical variability among patients with MPS VII (Tomatsu et al, 2009). …”

Mucopolysaccharidosis VII: A case report and literature review

“…The 3 phenotypes appear to be caused primarily by different combinations of mutant alleles at the β-glucuronicacid Glycosides Enzyme Gene (GUSB [7,17]. Some exonic point mutations, including p.L176F, p.R357X, p.P408S, p.P415L, and p.A619 V have been reported to be the most frequent mutations.…”

“…Mucopolysaccharidosis VII (MPS VII) is a rare autosomal recessive condition classified in the group of mucopolysaccharide storage diseases [1]. It results from a deficient function of the enzyme β glucuronidase (GUS: b-Dglucuronoside glucuronosohydrolase, EC 3.2.1.31; GUSB; MIM 611499) [2,3].…”