Mutations and Polymorphisms in GUSB Gene in Mucopolysaccharidosis VII (Sly Syndrome)

Mucopolysaccharidosis VII (MPS VII; Sly syndrome) is an autosomal recessive disorder caused by a deficiency of beta-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.