Categories: Lysosomal storage disease

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 252500 (trait) , 607840 (gene) , 252600 (trait)

Links to MONDO diseases: No links.

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)

Genetic engineering: Unknown
Have human generated variants been created, e.g. through genetic engineering and gene editing

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: