Mucopolysaccharidosis type VI in a Miniature Poodle-type dog caused by a deletion in the arylsulphatase B gene.

AIM: To investigate and characterise an inborn error of metabolism in a dog with skeletal and ocular abnormalities. METHODS: A 2.5-year-old small male Miniature Poodle-like dog was presented with gross joint laxity and bilateral corneal opacities. Clinical examination was augmented by routine haematology, serum chemistry, radiographs, pathology, enzymology and molecular genetic studies. Euthanasia was requested when the dog was 3 years of age because of progressively decreasing quality of life. RESULTS: Radiology revealed generalised epiphyseal dysplasia, malformed vertebral bodies, luxation/subluxation of appendicular and lumbosacral joints with hypoplasia of the odontoid process and hyoid apparatus. These clinical and radiographic findings, together with a positive urinary Berry spot test for mucopolysaccharides, and metachromatic granules in leucocytes, were indicative of a mucopolysaccharidosis (MPS), a lysosomal storage disease. Histological lesions included vacuolation of stromal cells of the cornea, fibroblasts, chondrocytes, macrophages and renal cells. The brain was essentially normal except for moderate secondary Wallerian-type degeneration in motor and sensory tracts of the hind brain. Dermatan sulphate-uria was present and enzymology revealed negligible activity of N-acetylgalactosamine-4-sulphatase, also known as arylsulphatase B, in cultured fibroblasts and liver tissue. A novel homozygous 22 base pair (bp) deletion in exon 1 of this enzyme's gene was identified (c.103_124del), which caused aframe-shift and subsequent premature stop codon. The "Wisdom pure breed-mixed breed" test reported the dog as a cross between a Miniature and Toy Poodle. CONCLUSIONS: The clinicopathological features are similar to those of MPS type VI as previously described in dogs, cats and other species, and this clinical diagnosis was confirmed by enzymology and molecular genetic studies. This is an autosomal recessively inherited lysosomal storage disease. CLINICAL RELEVANCE: The prevalence of MPS VI in Miniature or Toy Poodles in New Zealand and elsewhere is currently unknown. Due to the congenital nature of the disorder, malformed pups may be subject to euthanasia without investigation and the potential genetic problem in the breed may not be fully recognised. The establishment of a molecular genetic test now permits screening for this mutation as a basis to an informed breeding policy.

Animal model studies of allelism: characterization of arylsulfatase B mutations in homoallelic and heteroallelic (genetic compound) homozygotes with feline mucopolysaccharidosis VI.

The identification of a second structural gene mutation at the feline arylsulfatase B locus (MPS VIb) provided the opportunity to investigate the expression of allelism by characterization of the residual enzymatic activity in feline mucopolysaccharidosis VI, an animal analogue of human Maroteaux-Lamy syndrome. Matings were designed to produce affected homozygotes who were homoallelic for the MPS VIa and MPS VIb mutations or heteroallelic genetic compounds (MPS VIa/VIb). The physicokinetic and immunological properties of the partially purified residual hepatic arylsulfatase B isozymes from the affected homoallelic and heteroallelic cats were compared to those of the normal feline enzyme. The residual hepatic arylsulfatase B activities from the inbred MPS VIa and MPS VIb homozygotes were distinguished by differences in physicokinetic and immunological properties. The newly identified mutant isozyme b had abnormal kinetic properties toward artificial and natural substrates, normal cryo- and thermostabilities, a normal molecular weight and an altered electrophoretic mobility. Polyacrylamide gel electrophoresis demonstrated that the mutant b subunits formed dimers with normal subunits in obligate heterozygotes (MPS VI+/b). In contrast, mutant isozyme a subunits from obligate MPS VIa/+ heterozygotes did not dimerize with the normal subunit, and the mutant and normal isozymes could be separated by anion exchange chromatography and polyacrylamide gel electrophoresis. Characterization of the partially purified residual hepatic arylsulfatase B activity from the heteroallelic homozygotes revealed the presence of both mutant isozymes a and b. The demonstration of two allelic mutations in the feline arylsulfatase B gene documented the occurrence of genetic heterogeneity in feline mucopolysaccharidosis VI and permitted characterization of the enzymatic defect in homoallelic and heteroallelic (genetic compound) homozygotes, providing a model for the study of allelism in human genetic disorders.