title: Segregation analysis in a family at risk for the Maroteaux-Lamy syndrome conclusively reveals c.1151G>A (p.S384N) as to be a polymorphism.
abstract: Maroteaux-Lamy syndrome is an autosomal-recessive disorder due to the deficit of the lysosomal enzyme, arylsulfatase B (ARSB). Among the numerous genomic lesions reported till now, the sequence variant, c.1151G>A (p.S384N), has been associated with a severe phenotype in more than 10% of the patients. We now report the first in vivo demonstration of the polymorphic nature of p.S384N, revealed during the segregation analysis in a family at risk for Maroteaux-Lamy syndrome. The proband, compound heterozygous for c.[944G>A]+[245T>G] (p.[R315Q]+[L82R]), did not carry the p.S384N change, which was instead present in two healthy members of the family, in trans with the causative mutations, p.R315Q and p.L82R, respectively. The hypothesis that p.S384N was a polymorphism was further addressed by reverse dot-blot analysis of 400 control alleles, estimating an allele frequency of 4.5%. To predict the consequences of p.R315Q, p.L82R and p.S384N, we also modeled and compared the three amino-acid changes in the three-dimensional ARSB structure. The in silico analysis predicted a local protein misfolding in the presence of p.R315Q and p.L82R. On the contrary, no evident problem was predicted in the case of p.S384N, occurring on the protein surface, far from the active site. Overall, these findings strongly support the hypothesis that the non-synonymous change p.S384N is a polymorphism. Moreover, our results emphasize the need for caution in drawing conclusions from a novel variant allele before screening at least 50 healthy control subjects.
authors.affiliation: Department of Pediatrics and Centre for Rare Diseases, University of Padova, Padova, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Zanetti
authors.forename: Elena
authors.initials: E
authors.lastname: Ferraresi
authors.forename: Luigi
authors.initials: L
authors.lastname: Picci
authors.forename: Mirella
authors.initials: M
authors.lastname: Filocamo
authors.forename: Rossella
authors.initials: R
authors.lastname: Parini
authors.forename: Camillo
authors.initials: C
authors.lastname: Rosano
authors.forename: Rosella
authors.initials: R
authors.lastname: Tomanin
authors.forename: Maurizio
authors.initials: M
authors.lastname: Scarpa
mesh_terms: D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D008297:Male; D008958:Models, Molecular; D009085:Mucopolysaccharidosis IV / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics*; D020125:Mutation, Missense; D020051:N-Acetylgalactosamine-4-Sulfatase / Q000737:chemistry / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D011487:Protein Conformation; D012307:Risk Factors; D013577:Syndrome
chemical_list: D020051:N-Acetylgalactosamine-4-Sulfatase