Mucolipidosis type II (GNTPAB-related)

Gene: GNTPAB

Transmission: Autosomal recessive

For an autosomal recessive genetic disease an animal must have two copies of the mutation in question to be at risk of developing the disease.  Both parents of an affected animal must be carriers of at least one copy of the mutation.  Animals that have only one copy of the mutation are not at risk of developing the disease but are carrier animals that can pass the mutation on to future generations.

Mutation: Substitution, GNTPAB gene: c.2644 C>T, p.(Gln882 STOP), exon13, Chr.B4.

Medical system: Neuropathy, skeletal (lysosomal storage disease)

Breed: Domestic Cat shorthair

Age of onset of symptoms: 2-3 months; lethal by 7 months

A 7-month old domestic shorthaired cat presented with poor growth, ataxia, facial dysmorphia, and skeletal abnormalities reminiscent of lysosomal storage diseases (mucopolysaccaridosis) seen in humans and other species. Enzyme studies showed reduced cell levels of lysosomal hydrolases, while histological studies showed cell inclusion bodies typical of I-cell disease (mucolipidosis type II) seen in humans.

Although the affected cat was deceased, breeding of a normal half sibling male cat allowed the establishment of a research colony for further study of the disease.  Molecular studies established a causal mutation in the GNTPAB gene, which codes for an enzyme involved in delivering hydrolase enzymes to the lysosome. Lysozyme activity is thus deficient, resulting in lysosomal accumulation of cholesterol, phospholipids, glycosaminoglycans (GAGs) and other biomolecules, the cellular morphology described as I-cells, and the clinical and developmental features of mucolipidosis type II.

Mucolipidosis type II in cats is a very rare disease arising from natural mutations. Spread of the causal mutation is limited due to death before the age of reproduction.  This disease is of academic interest as a model for human disease but is not a clinical concern to cat breeders or veterinarians.

References:

OMIA link: [1248-9685]

Lyons LA. (2024) Genetic testing: practical dos and don’ts for cats.  J Feline medicine and surgery 26:1-13.  [pm/39648935]

Khan SA, Tomatsu SC. (2020) Mucolipidoses overview: Past, present, and future. Int J Mol Sci 21:6812.  [pm/32957425]

Wang P, Mazrier H, Caverly Rae J, et al. (2018) A GNPTAB nonsense variant is associated with feline mucolipidosis II (I-cell disease). BMC Vet Res 14:416. [pm/30591066]

Mazrier H, Van Hoeven M, Wang W, et al. (2003) Inheritance, biochemical abnormalities, and clinical features of feline mucolipidosis II: the first animal model of human I-cell disease.  J Hered. 94(5):363-373. [pm/14557388]

Bosshard NU, Hubler M, Arnold S, et al. (1996) Spontaneous mucolipidosis in a cat – an animal model of human I-cell disease. Veterinary Pathology 33:1-13. [pm/8826001]

With contributions by: Stephanie Gilbert and Anastasia Gilbert, Class of 2030, Faculty of Veterinary Medicine, University of Montreal.