Mutational analysis of 105 mucopolysaccharidosis type VI patients.
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.
Karageorgos
Litsa
L
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
Brooks
Doug A
DA
Pollard
Anthony
A
Melville
Elizabeth L
EL
Hein
Leanne K
LK
Clements
Peter R
PR
Ketteridge
David
D
Swiedler
Stuart J
SJ
Beck
Michael
M
Giugliani
Roberto
R
Harmatz
Paul
P
Wraith
James E
JE
Guffon
Nathalie
N
Leão Teles
Elisa
E
Sá Miranda
M Clara
MC
Hopwood
John J
JJ
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
D006025:Glycosaminoglycans; C020341:glucosaminoglycans; D020051:N-Acetylgalactosamine-4-Sulfatase