In other species: dog

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: 1999

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: This lysosomal storage disease was first described in cats (a black domestic short-haired cat from Switzerland) by Gitzelmann et al. (1994), who reported a lack of the enzyme beta-glucuronidase.

Inheritance: No breeding data available, but presumably autosomal recessive.

Molecular basis: By cloning and sequencing a very likely comparative candidate gene (based on the homologous human disorder), Fyfe et al. (1999) reported the molecular basis of this disorder in cats to be a missense mutation in the GUSB gene encoding the enzyme beta-glucuronidase. The authors reported that this mutation is "a G-to-A transition in the affected cat cDNA that predicted an E351K substitution, destroyed a BssSI site, and eliminated GUSB enzymatic activity in expression studies". According to the variant nomenclature of the year 2013 this corresponds to c.1051G>A or p.E351K. Wang et al. (2015) reported another causal mutation: "2 unique single base transitions (c.1421T>G and c.1424C>T) in exon 9, altering 2 adjacent codons (p.Ser475Ala and p.Arg476Trp). These amino acid changes are in a highly conserved domain of the GUSB protein and nontolerable to maintain function. Moreover, the p.Arg476Trp mutation previously has been identified in human patients."

Clinical features: (From Gitzelmann et al., 1994) The affected cat was presented at 12-14 weeks of age, with walking difficulties and an enlarged abdomen. He was small for his age, and showed intense licking. He was, however, active and attentive. His face was broad, cheeks were high, and nose was short. There were signs of frontal bossing, corneal clouding, plump front paws with inside rotation, and mild thickening of the skin, especially over the paws. His ears were small and their tips were distorted. Other signs included lengthened tongue, extended abdomen, and funnel-shaped lower thoracic opening. He walked with his weight shifted to his front paws. The clinical course was progressive: the rear legs showed reduced proprioceptivity and no tactile reflexes, hyperreflexia (patellar and tibialis cranialis reflexes), and positive crossed extensor reflexes. Cuticular reflexes were not elicited. Grand mal seizures lasted up to 20 seconds and could be evoked by stimulation of the skin over his back. His neck became stiff, and walking became almost impossible. Excessive scaling of the skin occurred. Patellae could be dislocated with ease; cruciate ligaments were lax. Tongue and first digits became irritated from excessive licking. Growth decelerated. He was euthanased at 5.5-6 months.

Pathology: (From Gitzelmann et al., 1994) Activity of beta-glucuronidase was absent from leucocytes, and was markedly reduced in fibroblasts. Neutrophils were granulated; lymphocytes vacuolated. Positive urine test for sulfated glycosaminoglycans. Foam cells in almost all organs; pancytic storage of floccular material characteristic of mucopolysaccharides. Stored sphingolipids in the form of zebra bodies in ganglion cells of the central nervous system and in smoothh muscle cells of blood vessels.

Associated gene: