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.

Molecular Analysis of Turkish Maroteaux-Lamy Patients and Identification of One Novel Mutation in the Arylsulfatase B (ARSB) Gene

“…In fact, all patients carrying the mutations p.L321P or c.1036delG, presented also the polymorphism p.V358M. The allele frequency was 36.1%, slightly higher than that (32%) found in the population previously analyzed (Karageorgos et al 2007b). Also the frequency of the allele p.S384N is higher with respect to the frequency detected by Karageorgos (16.6% versus 6.3%), although in that paper it was erroneously identified as pathological mutation.…”

“…Both mutations were previously described (Karageorgos et al 2007b): the p.D54N was detected in a homozygote and in a compound heterozygote patients both of Portuguese origin; this mutation, directly affecting the ARSB catalytic site, might result in an early-onset and rapidly progressing pathology. The p.W353R mutation was found in a compound heterozygote with a non-specified phenotype.…”

“…Then it was reported, again in homozygosis, in one patient, with a non-specified phenotype (Karageorgos et al 2007b). …”

“…It was first reported in a homozygote German patient with a very high level of urinary GAG (699 mg/ml creatinine) who showed symptoms of a rapidly progressing disease (Karageorgos et al 2007b). …”

“…Most mutations are private or restricted to a small number of subjects. Moreover, some alleles are particularly frequent in certain populations like p. R315Q in Portugal (Karageorgos et al 2007b) and p. R152W in Russia (Voskoboeva et al 2000). For some genetic variations a clear genotype-phenotype correlation was established (Karageorgos et al 2007b), but in most cases this is not the rule.…”