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Mucopolysaccharidosis Type VII (GUSB gene, Brazilian Terrier)

Mucopolysaccharidosis Type VII (GUSB gene, Brazilian Terrier)

Mucopolysaccharidosis VII is a lysosomal storage disease caused by mutations in the GUSB gene encoding beta-glucuronidase responsible for the degradation of mucopolysaccharides (glycosaminoglycans) in the lysosome.

Symptoms

Mucopolysaccharidosis VII in dogs is characterized by a number of symptoms. In the first month of life, affected dogs present with facial abnormalities, low-set ears and broad thorax. Corneal opacity becomes evident at 8 weeks, and they also have disproportionately large heads. Excess mucopolysaccharides are detected in the urine. Between the second and fifth month, dogs experience difficulty in standing, joint problems and significant epiphyseal dysplasia. They may also experience cardiac abnormalities, such as mitral insufficiency and aortic aneurysm.

Disease Management

At present, no definitive cure has been found for mucopolysaccharidosis VII. Management of the disease focuses on supportive care and symptomatic treatment to control pain. However, cases have been reported in which gene therapy, using a retroviral vector expressing canine beta-glucuronidase, has been shown to be effective in improving disease symptoms. Genetic testing and breeding strategies are recommended to avoid inheritance of the disease in future generations.

Genetic basis

This disease follows an autosomal recessive mode of inheritance. Autosomal recessive inheritance means that the dog, regardless of sex, must receive two copies of the mutation or pathogenic variant to be at risk of developing the disease. Both parents of an affected dog must carry at least one copy of the mutation. Animals with only one copy of the mutation are not at increased risk of developing the disease, but may pass the mutation on to future generations. Breeding between dogs carrying genetic variants that can cause disease, even if they do not show symptoms, is not recommended.

Technical report

Mucopolysaccharidosis VII is characterized by the accumulation of glycosaminoglycans in lysosomes due to beta-glucuronidase deficiency encoded by the GUSB gene. Beta-glucuronidase is an acid hydrolase that breaks down glucosaminoglycans containing glucuronate. Lack or dysfunction of this enzyme results in the accumulation of glycosaminoglycans in lysosomes, leading to the characteristic symptoms of the disease. A nonsense mutation (c.866C>T) affecting a highly conserved domain of beta-glucuronidase has been identified in the Brazilian Terrier breed. This mutation probably alters the structure or function of the protein, as affected dogs show virtually no residual enzyme activity (0.2%). In addition, an earlier onset of symptoms has been observed in Brazilian Terriers, indicating the severity of the mutation and its impact on enzyme activity.

Most affected breeds

Brazilian Terrier

Bibliography

Hytönen MK, Arumilli M, Lappalainen AK,et al. A novel GUSB mutation in Brazilian terriers with severe skeletal abnormalities defines the disease as mucopolysaccharidosis VII. PLoS One. 2012;7(7):e40281.