title: Mutation and polymorphism spectrum of the GALNS gene in mucopolysaccharidosis IVA (Morquio A).
abstract: Mucopolysaccharidosis IVA (MPS IVA; Morquio A disease) is an autosomal-recessive disorder caused by a deficiency of lysosomal N-acetylgalactosamine-6-sulfate sulfatase (GALNS; E.C.3.1.6.4). GALNS is required to degrade glycosaminoglycans, keratan sulfate (KS), and chondroitin-6-sulfate. Accumulation of undegraded substrates in lysosomes of the affected tissues leads to a systemic bone dysplasia. We summarize information on 148 unique mutations determined to date in the GALNS gene, including 26 novel mutations (19 missense, four small deletions, one splice-site, and two insertions). This heterogeneity in GALNS gene mutations accounts for an extensive clinical variability within MPS IVA. Seven polymorphisms that cause an amino acid change, and nine silent variants in the coding region are also described. Of the analyzed mutant alleles, missense mutations accounted for 78.4%; small deletions, 9.2%; nonsense mutation, 5.0%; large deletion, 2.4%; and insertions, 1.6%. Transitional mutations at CpG dinucleotides accounted for 26.4% of all the described mutations. The importance of the relationship between methylation status and distribution of transitional mutations at CpG sites at the GALNS gene locus was elucidated. The three most frequent mutations (over 5% of all mutations) were represented by missense mutations (p.R386C, p.G301C, and p.I113F). A genotype/phenotype correlation was defined in some mutations. Missense mutations associated with a certain phenotype were studied for their effects on enzyme activity and stability, the levels of blood and urine KS, the location of mutations with regard to the tertiary structure, and the loci of the altered amino acid residues among sulfatase proteins.
authors.affiliation: Department of Pediatrics, Pediatric Research Institute, Saint Louis University, St. Louis, Missouri 63110-2586, USA. tomatsus@slu.edu
authors.forename: Shunji
authors.initials: S
authors.lastname: Tomatsu
authors.forename: Adriana M
authors.initials: AM
authors.lastname: Montaño
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Nishioka
authors.forename: Monica A
authors.initials: MA
authors.lastname: Gutierrez
authors.forename: Olga M
authors.initials: OM
authors.lastname: Peña
authors.forename: Georgeta G
authors.initials: GG
authors.lastname: Tranda Firescu
authors.forename: Patricia
authors.initials: P
authors.lastname: Lopez
authors.forename: Seiji
authors.initials: S
authors.lastname: Yamaguchi
authors.forename: Akihiko
authors.initials: A
authors.lastname: Noguchi
authors.forename: Tadao
authors.initials: T
authors.lastname: Orii
mesh_terms: D000818:Animals; D002811:Chondroitinsulfatases / Q000737:chemistry / Q000235:genetics*; D018899:CpG Islands; D019175:DNA Methylation; D005838:Genotype; D006801:Humans; D007632:Keratan Sulfate / Q000378:metabolism; D051379:Mice; D009085:Mucopolysaccharidosis IV / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D009154:Mutation; D011110:Polymorphism, Genetic; D017434:Protein Structure, Tertiary
chemical_list: D007632:Keratan Sulfate; D002811:Chondroitinsulfatases; C102295:GALNS protein, human; C491158:Galns protein, mouse