Identification of molecular defects in Italian Sanfilippo A patients including 13 novel mutations

Natale, Paola Di; Balzano, Nicola; Esposito, Sabrina; Villani, Guido

doi:10.1002/(sici)1098-1004(1998)11:4<313::aid-humu9>3.0.co;2-p

Cited by 60 publications

(46 citation statements)

References 18 publications

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“…30 The relative instability of CpG dinucleotides might also contribute to some mutations arising independently in the same codon which was found in R565 W/P, R643 C/H 10 and R674 C/H. 3 Similar multiple mutations were also observed in MPS IIIA (amino acids R74 and R377), 23,31,32 , MPS I, 33 and disorders other than lysosomal storage diseases. [34][35][36] Two of the six arginine codons constitute CpG dinucleotides and in the above amino acid exchanges these two codons are mutated.…”

Section: Discussionsupporting

confidence: 76%

Sanfilippo type B syndrome (mucopolysaccharidosis III B): allelic heterogeneity corresponds to the wide spectrum of clinical phenotypes

et al. 1999

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Sanfilippo B syndrome (mucopolysaccharidosis IIIB, MPS IIIB) is caused by a deficiency ofα-N-acetylglucosaminidase, a lysosomal enzyme involved in the degradation of heparan sulphate. Accumulation of the substrate in lysosomes leads to degeneration of the central nervous system with progressive dementia often combined with hyperactivity and aggressive behaviour. Age of onset and rate of progression vary considerably, whilst diagnosis is often delayed due to the absence of the pronounced skeletal changes observed in other mucopolysaccharidoses. Cloning of the gene and cDNA encoding α-N-acetylglucosaminidase enabled a study of the molecular basis of this syndrome. We were able to identify 31 mutations, 25 of them novel, and two polymorphisms in the 40 patients mostly of Australasian and Dutch origin included in this study. The observed allellic heterogeneity reflects the wide spectrum of clinical phenotypes reported for MPS IIIB patients. The majority of changes are missense mutations; also four nonsense and nine frameshift mutations caused by insertions or deletions were identified. Only five mutations were found in more than one patient and the observed frequencies are well below those observed for the common mutations in MPS IIIA. R643C and R297X each account for around 20% of MPS IIIB alleles in the Dutch patient group, whilst R297X, P521L, R565W and R626X each have a frequency of about 6% in Australasian patients. R643C seems to be a Dutch MPS IIIB allele and clearly confers the attenuated phenotype. One region of the gene shows a higher concentration of mutations, probably reflecting the instability of this area which contains a direct repeat. Several arginine residues seem to be 'hot-spots' for mutations, being affected by two or three individual base pair exchanges.

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Section: Discussionsupporting

confidence: 76%

Sanfilippo type B syndrome (mucopolysaccharidosis III B): allelic heterogeneity corresponds to the wide spectrum of clinical phenotypes

et al. 1999

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“…For example, R245H accounts for 56% of mutant alleles in MPS-IIIA patients in The Netherlands (13), with S66W showing prevalence in Italy with 33% of alleles (11); R74C alone accounts for more than 50% of alleles in MPS-IIIA patients in Poland (10); and delC1091 accounts for almost half of the mutations in Spanish MPS-IIIA patients (12). Despite an increased effort to identify mutations in the NS gene, interpretation of clinical phenotype remains difficult, with identical genotypes often manifesting within a broad clinical spectrum (11). These previous studies have relied on clinical analysis of patient data in order to determine the effect of identified mutations on the activity of the wild type enzyme.…”

Section: Sulfamidase (Ns)mentioning

confidence: 95%

“…S66W-S66W represents the most common alteration in the Italian MPS-IIIA population, accounting for 33% of total alleles (11). Interestingly, all six patients described (11) originate from Sardinia, and five are homozygous for S66W, suggesting that these subjects may have been derived from a common founder.…”

Section: Correlation Between Mutant Protein Expression Andmentioning

confidence: 99%

“…The presence of the common polymorphism R456H is discounted in a study with all patients homozygous for S66W and showing variable clinical symptoms negative for R456H (11). Quantification studies of S66W in patient fibroblasts 2 show that there is a residual level of sulfamidase that has a similarly low specific activity, supporting the expression data presented in this paper.…”

Section: Correlation Between Mutant Protein Expression Andmentioning

confidence: 99%

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Expression and Characterization of Wild Type and Mutant Recombinant Human Sulfamidase

Perkins

Byers

Yogalingam

et al. 1999

Journal of Biological Chemistry

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Mucopolysaccharidosis IIIA (MPS-IIIA) is an autosomal recessive lysosomal storage disorder caused by the deficiency of sulfamidase (NS; EC 3.10.1.1), resulting in defective degradation and storage of heparan sulfate. This paper reports the production and characterization of monoclonal and polyclonal antibodies against recombinant human sulfamidase (rhNS) to quantitate and characterize normal and mutant sulfamidase produced from the wild type NS expression vector. Glycosylation and phosphorylation studies of immunoprecipitated rhNS show that all five potential glycosylation sites are utilized, with three high mannose/hybrid oligosaccharides and two simpler chains, with at least one functional mannose 6-phosphate group. An NS quantification system was developed to determine the effect of the three most common and severe patient mutations: S66W (Italy), R74C (Poland), and R245H (The Netherlands). The quantity and specific activity of expressed mutant rhNS was significantly lower than expressed normal rhNS, with 0.3, 0.2, and 0.05% of normal rhNS produced and 15, 17, and 83% of normal specific activity for S66W, R74C, and R245H observed, respectively. The recent structural elucidation of N-acetylgalactosamine-4-sulfatase was utilized to postulate the effect on the structure-function relationship of NS. The characterization of normal and mutated rhNS has relevance for efficient diagnosis and therapeutic developments for MPS-IIIA patients.

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“…7 To date, 46 different mutations have been identified in Sanfilippo A patients,6 8-13 several of which have been found at high frequencies in particular populations. The R245H, R74C, 1091delC, and S66W were the most frequent mutations in the Dutch (56.7%),11 Polish (56%),8 Spanish (45.5%),13 and Italian (33%)12 populations, respectively. Several polymorphisms have been identified in the sulphamidase gene including R456H, which has a high frequency of 55% in the normal Australian population 9.…”

mentioning

confidence: 99%

Mutational analysis of Sanfilippo syndrome type A (MPS IIIA): identification of 13 novel mutations

Beesley¹,

Young²,

Vellodi³

et al. 2000

Journal of Medical Genetics

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Identification of molecular defects in Italian Sanfilippo A patients including 13 novel mutations

Cited by 60 publications

References 18 publications

Sanfilippo type B syndrome (mucopolysaccharidosis III B): allelic heterogeneity corresponds to the wide spectrum of clinical phenotypes

Sanfilippo type B syndrome (mucopolysaccharidosis III B): allelic heterogeneity corresponds to the wide spectrum of clinical phenotypes

Expression and Characterization of Wild Type and Mutant Recombinant Human Sulfamidase

Mutational analysis of Sanfilippo syndrome type A (MPS IIIA): identification of 13 novel mutations

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