OMIA 001248-9685 : Mucolipidosis II in Felis catus

Possibly relevant human trait(s) and/or gene(s) (MIM number): 252500

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2018

Cross-species summary: Mucolipidosis II (also known as I-cell disease) is a lysosomal storage disease in which there is a buildup (storage) of a range of macromolecules (which remain visible in the form of lysosomal inclusions: so-called I-cells), due to the lack of a range of lysosomal enzymes whose task is to break down the macromolecules into their constituents. Unlike a 'typical' lysosomal storage disease which is due to the lack of a particular lysosomal enzyme, I-cell disease results from the lack of the Golgi enzyme UDP-N-acetylglucosamine-1-phosphotransferase (GlcNAc-phosphotransferase) (EC 2.7.8.17), whose task is to attach phosphate groups to mannose residues of soluble lysosomal enzymes. The consequent lack of a mannose-6-phosphate (M-6-P) recognition site means that the enzymes cannot be transported via M-6-P receptors to the lysosomes, ending up instead in extracellular space. Thus, lysosomes are deficient in a range of lysosomal enzymes, while serum and extracellular fluids show elevated activity of these enzymes.

Species-specific description: The first case of I-cell disease reported in any animal was by Bosshard et al. (1996), who described an affected female domestic short-haired cat. A colony has been established at the Laboratory of Pathology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia. A second case was also reported in 1996, by Hubler et al. (1996).

Inheritance: Available breeding data are consistent with autosomal recessive inheritance (Mazrier et al., 2003).

Molecular basis: Affected cats were homozygous for a single base substitution (c.2644C > T) in exon 13 of GNPTAB, changing the codon for glutamine [CAG] to a premature stop codon [TAG] (p.Gln882*). This variant predicts severe truncation and complete dysfunction of the GNPTAB enzyme (Wang et al., 2018)

Clinical features: (From Bosshard et al. 1996) Facial dysmorphism, large paws in relation to body size, dysostosis multiplex, poor growth, abnormal gait, extreme stiffness of skin, reduced mobility of spine, developmental delay, congenital hip dysplasia, retinal changes, and a rapid course of deterioration. Presented at 7 months; euthanased at 11 months.

Pathology: The Golgi enzyme UDP-N-acetylglucosamine-1-phosphotransferase was deficient in leukocytes and cultured fibroblasts. Twelve lysosomal hydrolases showed abnormally low activity in fibroblasts but markedly elevated activity in blood plasma. Lysosomal inclusions (comprising oligosaccharides, mucopolysaccharides and lipids) were present in cells of mesenchymal origin - fibroblasts, endothelial cells, and chondrocytes.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
GNPTAB N-acetylglucosamine-1-phosphate transferase, alpha and beta subunits Felis catus B4 NC_018729.3 (124487973..124414189) GNPTAB Homologene, Ensembl, NCBI gene

Variants

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WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.

Breed(s) Variant Phenotype Gene Allele Type of Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Year Published PubMed ID(s) Acknowledgements
Domestic Shorthair Mucolipidosis II GNPTAB nonsense (stop-gain) Felis_catus_6.2 B4 c.2644C>T p.Gln882* Wang et al. (2018): "NCBI-RefSeq accession no. XM_003989173.4, Gene ID: 101100231" 2018 30591066

References


Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
2018 Wang, P., Mazrier, H., Caverly Rae, J., Raj, K., Giger, U. :
A GNPTAB nonsense variant is associated with feline mucolipidosis II (I-cell disease). BMC Vet Res 14:416, 2018. Pubmed reference: 30591066. DOI: 10.1186/s12917-018-1728-1.
2003 Mazrier, H., Van Hoeven, M., Wang, P., Knox, VW., Aguirre, GD., Holt, E., Wiemelt, SP., Sleeper, MM., Hubler, M., Haskins, ME., Giger, U. :
Inheritance, biochemical abnormalities, and clinical features of feline mucolipidosis II: the first animal model of human I-cell disease. J Hered 94:363-73, 2003. Pubmed reference: 14557388.
1996 Bosshard, N.U., Hubler, M., Arnold, S., Briner, J., Spycher, M.A., Sommerlade, H.J., Vonfigura, K., Gitzelmann, R. :
Spontaneous mucolipidosis in a cat - an animal model of human I-cell disease Veterinary Pathology 33:1-13, 1996. Pubmed reference: 8826001.
Hubler, M., Haskins, M.E., Arnold, S., Kaserhotz, B., Bosshard, N.U., Briner, J., Spycher, M.A., Gitzelmann, R., Sommerlade, H.J., Vonfigura, K. :
Mucolipidosis type II in a domestic shorthair cat Journal of Small Animal Practice 37:435-441, 1996. Pubmed reference: 8887204.

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