In other species: domestic cat

Categories: Lysosomal storage disease

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 253220 (trait) , 611499 (gene)

Links to relevant human diseases in MONDO:

• MONDO:0009662: mucopolysaccharidosis type 7

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 1998

Cross-species summary: Mucopolysaccharidosis VII is a lysosomal storage disease in which there is a buildup (storage) of mucopolysaccharides (glycosaminoglycans), due to the lack of the lysosomal enzyme acid hydrolase beta-glucuronidase (EC 3.2.1.31).

Species-specific description: Mucopolysaccharidosis VII is a lysosomal storage disease characterized by accumulation of undegraded glycosaminoglycans (dermatan, heparan, and chondroitin sulfates) in lysosomes. Clinical signs include facial dysmorphia, diffuse corneal clouding, appendicular and axial skeletal lesions, and glycosaminoglycans in urine. Affected animals are deficient in the enzyme beta-glucuronidase, which is a lysosomal acid hydrolase. Affected animals have very low enzyme activity compared to normal animals, and carriers have 40-60% enzyme activity compared to normal animals. The mode of inheritance is autosomal recessive. The causative mutation is a G to A substitution in the gene coding for the hydrolase, beta-glucuronidase (GUSB). There is a test available to detect the causative mutation. Testing siblings of affected dogs is recommended. Breeding of carriers or affected dogs is not recommended. Edited by Mark Haskins, VMD, Ph.D

Mapping: By conducting a GWAS on 7 affected and 11 control Brazilian Terriers, each genotyped with the Illumina’s 22K SNP chip (yielding 16,595 SNPs for analysis), Hytönen et al. (2012) highlighted a region on chromosome CFA6. Subsequent homozygosity mapping narrowed the region to 13Mb, including more than 200 genes. [FN; 20 May 2013]

Molecular basis: By cloning and sequencing a very likely comparative candidate gene (based on the homologous disorder in humans and other mammals), Ray et al. (1998; Genomics 48:248-253) identified the initial causative mutation as a "guanosine to adenine base change at nucleotide position 559 in the canine cDNA sequence [that] causes an arginine to histidine substitution at amino acid position 166" of the gene coding for hydrolase beta-glucuronidase (GUSB). In Brazilian Terriers, Hytönen et al. (2012) sequenced the entire 13Mb candidate region from their GWAS (see Mapping section), and discovered that the disorder in this breed is due to a "missense mutation (c.866C>T) causing a pathogenic p.P289L change in a conserved functional domain of β-glucuronidase (GUSB)".

Clinical features: At 4 weeks of age, affected dogs show a shortened, broad face, low-set ears, and a laterally broad chest. By 8 weeks of age, diffuse corneal clouding is apparent. At 9 weeks of age, affected dogs are half as large as their normal littermates, but have disproportionately large heads. Polymorphonuclear leukocytes and lymphocytes from affected animals contain coarse cytoplasmic granules that stain with toluidine blue. Urine from affected animals contain excessive chondroitin 4- and 6-sulfates and dermatan and heparan sulfates. By 2 to 5 months of age, affected dogs have trouble standing but can move in sternal recumbency. Most joints are easily subluxated and crepitant, with swollen, fluctuant joint capsules filled with excessive synovial fluid. There is significant epiphyseal dysplasia. Cardiac abnormalities, primarily mitral insufficiency and aortic aneurism can be present but are variable (Haskins et al., 1991).

Pathology: Affected animals are deficient in the enzyme beta-glucuronidase, which is a lysosomal acid hydrolase. Affected animals have very low enzyme activity compared to normal animals, and carriers have 40-60% enzyme activity compared to normal animals. Signs are caused by accumulation of undegraded glycosaminoglycans in lysosomes (Ray et al., 1999). Affected animals exhibit a misshapen and narrowed trachea, thickening of the AV heart valve leaflets and chordae tendinae, thickened aortic arch, hyperplasia of synovial membranes, and erosion of the articular cartilage (Haskins et al., 1991). Cytoplasmic vacuoles are evident in neurons of the central nervous system, hepatocytes, Kupffer cells, keratocytes, retinal pigment epithelium, AV heart valve fibroblasts, aortic smooth muscle cells, leukocytes, chondrocytes, and synovial cells. These vacuoles are either empty or contain granular or lamellar material (Haskins et al., 1991).

Control: Testing siblings of affected dogs is recommended. Breeding of carriers or affected dogs is not recommended.

Genetic testing: There is a test available to detect the causative mutation.

Breeds: Brazilian Terrier (Dog) (VBO_0200231), German Shepherd Dog (Dog) (VBO_0200577).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: