Feline Mucopolysaccharidosis Type VI

Yogalingam, Gouri; Litjens, Tom; Bielicki, Julie; Crawley, Allison C.; Muller, Vivienne; Anson, Donald S.; Hopwood, John J.

doi:10.1074/jbc.271.44.27259

Cited by 68 publications

(39 citation statements)

References 26 publications

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“…However, a number of colony cats that had no clinical indications of MPS VI also had very low or, in some instances, undetectable 4S activity levels in their blood leukocytes despite being genotyped as normal with respect to the L476P mutation. These observations suggested the presence of a second mutation (10). This study describes the identification and molecular characterization of this second mutation as the missense mutation, D520N.…”

mentioning

confidence: 79%

“…The position and sequence of oligonucleotides used for PCR or PCR sequencing are listed in Table I of Ref. 10.…”

Section: Methodsmentioning

confidence: 99%

“…Mutation Analysis of the f4S cDNA-Prior to the identification of D520N, cats were only screened for the L476P mutation using a PCRbased screening method (10). Cat 237 was identified to be homozygous for the normal 4S allele at position 476 (Leu-476) via mutation analysis, but had no detectable leukocyte 4S activity.…”

Section: Methodsmentioning

confidence: 99%

“…A PCR-based screening method enabled the identification of L476P homozygous cats, D520N/L476P compound heterozygous cats, and D520N homozygous cats in the colony. Clinical assessments of these cats have previously demonstrated that the three genotypes are associated with a severe MPS VI phenotype, mild MPS VI phenotype, and normal phenotype, respectively (10,11). In this study, we determined the 35 S-labeled GAG storage and 4S activity levels in D520N/L476P compound heterozygous and D520N homozygous skin fibroblasts.…”

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confidence: 96%

“…When using animal models to evaluate therapy protocols, it may be advantageous to use species-specific material in an attempt to avoid the complication of immunological responses to foreign proteins. As an initial step toward speciesspecific enzyme and gene replacement therapy in the MPS VI cat, the feline 4S (f4S) cDNA has been isolated and recombinant enzyme expressed and characterized (10).…”

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confidence: 99%

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Mild Feline Mucopolysaccharidosis Type VI

Yogalingam

Hopwood

Crawley

et al. 1998

Journal of Biological Chemistry

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The missense mutation, L476P, in the N-acetylgalactosamine 4-sulfatase (4S) gene, has previously been shown to be associated with a severe feline mucopolysaccharidosis type VI (MPS VI) phenotype. The present study describes a second mutation, D520N, in the same MPS VI cat colony, which is inherited independently of L476P and is associated with a clinically mild MPS VI phenotype in D520N/L476P compound heterozygous cats. Biochemical and clinical assessment of L476P homozygous, D520N/L476P compound heterozygous, and D520N homozygous cats demonstrated that the entire range of clinical phenotypes, from severe MPS VI, to mild MPS VI, to normal are clustered within a narrow range of residual 4S activity from 0.5% to 4.6% of normal levels. When overexpressed in CHO-KI cells, the secreted form of D520N 4S was inactivated in neutral pH conditions. In addition, intracellular D520N 4S protein was rapidly degraded and corresponded to 37%, 14.5%, and 0.67% of normal 4S protein levels in the microsomal, endosomal, and lysosomal compartments, respectively. However, the specific activity of lysosomal D520N 4S was elevated 22.5-fold when compared with wild-type 4S. These results suggest that the D520N mutation causes a rapid degradation of 4S protein. The effect of this is partially ameliorated as a result of a significant elevation in the specific activity of mutant D520N 4S reaching the lysosomal compartment. The mucopolysaccharidoses (MPS)1 are a group of lysosomal storage disorders that involve the deficiency of specific enzymes required for the degradation of glycosaminoglycans (GAG). MPS VI is characterized by a deficiency of N-acetylgalactosamine 4-sulfatase (4S), which leads to the lysosomal accumulation and urinary excretion of the GAG dermatan sulfate (DS) (1). The severe MPS VI phenotype is characterized by growth retardation, coarse facial features, joint stiffness, corneal clouding, skeletal deformities, and organ and soft tissue involvement. As a result of DS storage in the heart valve and lung, the normal function of these organs is often compromised, leading to early death in affected individuals. The central nervous system does not appear to be affected, even in individuals with clinically severe MPS VI (2).Patients with MPS VI are diagnosed by elevated levels of DS in their urine and a substantial reduction or lack of 4S activity in cells such as peripheral blood leukocytes and cultured skin fibroblasts. The clinical phenotype of MPS VI patients ranges from severe to relatively mild and has generally been shown to correlate with urinary DS and residual 4S activity levels (2). Generally, patients manifest symptomology associated with MPS VI when their 4S protein and activity levels are 5% or less of normal controls (3).Currently, there is no safe and effective treatment available for MPS patients other than surgical intervention to alleviate symptoms whenever possible. MPS VI is a good candidate for both enzyme and gene replacement therapy protocols for a number of reasons. First, the complication of targeting r...

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mentioning

confidence: 79%

“…The position and sequence of oligonucleotides used for PCR or PCR sequencing are listed in Table I of Ref. 10.…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 96%

mentioning

confidence: 99%

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Mild Feline Mucopolysaccharidosis Type VI

Yogalingam

Hopwood

Crawley

et al. 1998

Journal of Biological Chemistry

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Mucopolysaccharidosis type VI: Structural and clinical implications of mutations in N-acetylgalactosamine-4-sulfatase

Litjens

Hopwood

2001

Hum. Mutat.

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Mucopolysaccharidosis type VI (MPS-VI) is an autosomal recessive lysosomal storage disorder caused by the deficiency of N-acetylgalactosamine-4-sulfatase (4S; or ARSB). Mutations in the 4S gene are responsible for 4S deficiency, which leads to the intralysosomal storage of partially degraded glycosaminoglycans, dermatan sulfate, and chondroitin 4-sulfate. To date, a total of 45 clinically relevant mutations have been identified in the human 4S gene. Missense mutations are the largest group, with 31 identified mutations. Nonsense mutations and small insertions or deletions comprise the remainder, with seven mutations each. Six polymorphisms have also been reported: two amino acid substitutions and four silent transitions. Mapping of the missense mutations onto the 4S structure shows that they are distributed throughout the three subunits of the mature 4S polypeptide. Mutations have been identified in active site residues, in residues adjacent to the active site, in potential substrate binding residues, in residues exposed on the surface, and in residues buried within the protein core. Missense mutations have also been identified in disulfide crosslinks. Molecular modeling of MPS-VI mutations onto the 4S structure suggests that the majority cause 4S deficiency via destabilization and the consequent reduction of 4S protein concentration. The vast majority of MPS-VI mutant alleles are either unique to a patient or are present in a small number of patients. So far, no common mutations have been described. Therefore, screening of the general population for MPS-VI alleles will be difficult.

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Identification and molecular characterization of α-L-iduronidase mutations present in mucopolysaccharidosis type I patients undergoing enzyme replacement therapy

et al. 2004

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Mucopolysaccharidosis type I (MPS I) is an autosomal recessive lysosomal storage disorder caused by a deficiency of alpha-L-iduronidase (IDUA). Mutations in the gene are responsible for the enzyme deficiency, which leads to the intralysosomal storage of the partially degraded glycosaminoglycans dermatan sulfate and heparan sulfate. Molecular characterization of MPS I patients has resulted in the identification of over 70 distinct mutations in the IDUA gene. The high degree of molecular heterogeneity reflects the wide clinical variability observed in MPS I patients. Six novel mutations, c.1087C>T (p.R363C), c.1804T>A (p.F602I), c.793G>C, c.712T>A (p.L238Q), c.1727+2T>A, and c.1269C>G (p.S423R), in a total of 14 different mutations, and 13 different polymorphic changes, including the novel c.246C>G (p.H82Q), were identified in a cohort of 10 MPS I patients enrolled in a clinical trial of enzyme-replacement therapy. Five novel amino acid substitutions and c.236C>T (p.A79V) were engineered into the wild-type IDUA cDNA and expressed. A p.G265R read-through mutation, arising from the c.793G>C splice mutation, was also expressed. Each mutation reduced IDUA protein and activity levels to varying degrees with the processing of many of the mutant forms also affected by IDUA. The varied properties of the expressed mutant forms of IDUA reflect the broad range of biochemical and clinical phenotypes of the 10 patients in this study. IDUA kinetic data derived from each patient's cultured fibroblasts, in combination with genotype data, was used to predict disease severity. Finally, residual IDUA protein concentration in cultured fibroblasts showed a weak correlation to the degree of immune response to enzyme-replacement therapy in each patient.

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Feline Mucopolysaccharidosis Type VI

Cited by 68 publications

References 26 publications

Mild Feline Mucopolysaccharidosis Type VI

Mild Feline Mucopolysaccharidosis Type VI

Mucopolysaccharidosis type VI: Structural and clinical implications of mutations in N-acetylgalactosamine-4-sulfatase

Identification and molecular characterization of α-L-iduronidase mutations present in mucopolysaccharidosis type I patients undergoing enzyme replacement therapy

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