Two mutations within a feline mucopolysaccharidosis type VI colony cause three different clinical phenotypes.

Crawley, Allison C.; Yogalingam, Gouri; Muller, Vivienne; Hopwood, John J.

doi:10.1172/jci935

Cited by 55 publications

(52 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Despite the presence of residual 4S activity (approximately 3.1% of normal 4S activity levels in cultured skin fibroblasts, Table I), adult D520N/L476P compound heterozygous cats contain marginally elevated levels of DS in their urine and increased lysosomal vacuolation in most chondrocytes, which is associated with variable degrees of degenerative joint disease. Lysosomal vacuolation was not observed in any other tissues (11). D520N homozygous cats, which contain higher levels of residual 4S activity (approximately 4.6% of normal 4S activity levels in cultured skin fibroblasts, Table I), also contain marginally elevated levels of urinary DS and lysosomal vacuolation in some chondrocytes.…”

Section: Discussionmentioning

confidence: 83%

“…D520N homozygous cats, which contain higher levels of residual 4S activity (approximately 4.6% of normal 4S activity levels in cultured skin fibroblasts, Table I), also contain marginally elevated levels of urinary DS and lysosomal vacuolation in some chondrocytes. The small increase in residual 4S activity (from 3.1% to 4.6% of normal levels) appears to be sufficient to prevent the occurrence of degenerative joint disease in D520N homozygous cats (11). Although D520N homozygous and D520N/L476P compound heterozygous cats contain low 4S activity, their normal growth and outward appearance (11) suggest that this residual 4S activity is sufficient to metabolize the majority of natural substrate in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…The small increase in residual 4S activity (from 3.1% to 4.6% of normal levels) appears to be sufficient to prevent the occurrence of degenerative joint disease in D520N homozygous cats (11). Although D520N homozygous and D520N/L476P compound heterozygous cats contain low 4S activity, their normal growth and outward appearance (11) suggest that this residual 4S activity is sufficient to metabolize the majority of natural substrate in vivo. This is encouraging for gene and enzyme replacement therapy protocols for severely affected MPS patients, for whom only a small amount of recombinant enzyme may be required to prevent the majority of somatic symptoms.…”

Section: Discussionmentioning

confidence: 99%

“…These results suggest that the D520N mutation, in combination with the L476P mutation or on its own, results in a significant defect in GAG turnover in skin fibroblasts. Despite a reduced rate of GAG metabolism in skin fibroblasts, the residual 4S activity present in these cats appears to prevent lysosomal vacuolation in skin tissue (11).…”

Section: Analysis Of 4s Activity and Gag Storage In Feline Skinmentioning

confidence: 91%

“…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.…”

mentioning

confidence: 96%

See 4 more Smart Citations

Mild Feline Mucopolysaccharidosis Type VI

Yogalingam

Hopwood

Crawley

et al. 1998

Journal of Biological Chemistry

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Analysis Of 4s Activity and Gag Storage In Feline Skinmentioning

confidence: 91%

mentioning

confidence: 96%

See 3 more Smart Citations

Mild Feline Mucopolysaccharidosis Type VI

Yogalingam

Hopwood

Crawley

et al. 1998

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

A rare lysosomal storage disorder: Feline mucopolysaccharidosis VII

Smith

Snead

Sukut

et al. 2022

Vet Record Case Reports

View full text Add to dashboard Cite

A 9‐week‐old, male domestic shorthair presented with a 2‐week history of progressive hindlimb weakness and reduction in normal play behaviour. At 17 weeks of age, the patient exhibited progressive hindlimb paresis and ataxia and had developed facial dysmorphia and bilateral corneal clouding, prompting investigation into a mucopolysaccharidosis disorder. Peripheral blood cytology, increased urinary glycosaminoglycan excretion and radiographic findings (generalised epiphyseal dysplasia, coxofemoral luxation and vertebral fusion) suggested mucopolysaccharidosis. Definitive diagnosis was obtained through serum enzymatic testing, which yielded a complete deficiency in β‐glucuronidase and increased compensatory activity in α‐L‐iduronidase and B‐arylsulfatase. This pattern was consistent with a diagnosis of feline mucopolysaccharidosis VII, and palliative therapy was initially implemented. The patient ultimately died at 21 months of age.

show abstract

Unraveling the Genetic Mysteries of the Cat: New Discoveries in Feline-Inherited Diseases and Traits

Lyons

Genomics of Disease

View full text Add to dashboard Cite

Two mutations within a feline mucopolysaccharidosis type VI colony cause three different clinical phenotypes.

Cited by 55 publications

References 29 publications

Mild Feline Mucopolysaccharidosis Type VI

Mild Feline Mucopolysaccharidosis Type VI

A rare lysosomal storage disorder: Feline mucopolysaccharidosis VII

Unraveling the Genetic Mysteries of the Cat: New Discoveries in Feline-Inherited Diseases and Traits

Contact Info

Product

Resources

About