title: Mutational analysis of 105 mucopolysaccharidosis type VI patients.
abstract: Mucopolysaccharidosis type VI (MPS VI; Maroteaux-Lamy syndrome) is a lysosomal storage disorder caused by mutations in the N-acetylgalactosamine-4-sulfatase (arylsulfatase B, ARSB) gene. ARSB is a lysosomal enzyme involved in the degradation of the glycosaminoglycans (GAG) dermatan and chondroitin sulfate. ARSB mutations reduce enzyme function and GAG degradation, causing lysosomal storage and urinary excretion of these partially degraded substrates. Disease onset and rate of progression is variable, producing a spectrum of clinical presentation. In this study, 105 MPS VI patients-representing about 10% of the world MPS VI population-were studied for molecular genetic and biochemical parameters. Direct sequencing of patient genomic DNA was used to identify ARSB mutations. In total, 83 different disease-causing mutations were found, 62 of which were previously unknown. The novel sequence changes included: 38 missense mutations, five nonsense mutations, 11 deletions, one insertion, seven splice-site mutations, and four polymorphisms. ARSB mutant protein and residual activity were determined on fibroblast extracts for each patient. The identification of many novel mutations unique to individuals/their families highlighted the genetic heterogeneity of the disorder and provided an appropriate cohort to study the MPS VI phenotypic spectrum. This mutation analysis has identified a clear correlation between genotype and urinary GAG that can be used to predict clinical outcome.
authors: Lysosomal Diseases Research Unit, Department of Genetic Medicine, Children, Youth and Women's Health Service, North Adelaide, South Australia, Australia. litsa.karageorgos@cywhs.sa.gov.au
authors: Litsa
authors: L
authors: Karageorgos
authors: Doug A
authors: DA
authors: Brooks
authors: Anthony
authors: A
authors: Pollard
authors: Elizabeth L
authors: EL
authors: Melville
authors: Leanne K
authors: LK
authors: Hein
authors: Peter R
authors: PR
authors: Clements
authors: David
authors: D
authors: Ketteridge
authors: Stuart J
authors: SJ
authors: Swiedler
authors: Michael
authors: M
authors: Beck
authors: Roberto
authors: R
authors: Giugliani
authors: Paul
authors: P
authors: Harmatz
authors: James E
authors: JE
authors: Wraith
authors: Nathalie
authors: N
authors: Guffon
authors: Elisa
authors: E
authors: Leão Teles
authors: M Clara
authors: MC
authors: Sá Miranda
authors: John J
authors: JJ
authors: Hopwood
mesh_terms: D000293:Adolescent; D000328:Adult; D017677:Age Distribution; D002478:Cells, Cultured; D002648:Child; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005787:Gene Frequency; D018740:Genetic Heterogeneity; D005820:Genetic Testing; D006025:Glycosaminoglycans / Q000652:urine; D006801:Humans; D008875:Middle Aged; D009087:Mucopolysaccharidosis VI / Q000235:genetics*; D020051:N-Acetylgalactosamine-4-Sulfatase / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
chemical_list: D006025:Glycosaminoglycans; C020341:glucosaminoglycans; D020051:N-Acetylgalactosamine-4-Sulfatase