Mucolipidoses Overview: Past, Present, and Future

Abstract

Mucolipidosis II and III (ML II/III) are caused by a deficiency of uridine-diphosphate N-acetylglucosamine: lysosomal-enzyme-N-acetylglucosamine-1-phosphotransferase (GlcNAc-1-phosphotransferase, EC2.7.8.17), which tags lysosomal enzymes with a mannose 6-phosphate (M6P) marker for transport to the lysosome. The process is performed by a sequential two-step process: first, GlcNAc-1-phosphotransferase catalyzes the transfer of GlcNAc-1-phosphate to the selected mannose residues on lysosomal enzymes in the cis-Golgi network. The second step removes GlcNAc from lysosomal enzymes by N-acetylglucosamine-1-phosphodiester α-N-acetylglucosaminidase (uncovering enzyme) and exposes the mannose 6-phosphate (M6P) residues in the trans-Golgi network, in which the enzymes are targeted to the lysosomes by M6Preceptors. A deficiency of GlcNAc-1-phosphotransferase causes the hypersecretion of lysosomal enzymes out of cells, resulting in a shortage of multiple lysosomal enzymes within lysosomes. Due to a lack of GlcNAc-1-phosphotransferase, the accumulation of cholesterol, phospholipids, glycosaminoglycans (GAGs), and other undegraded substrates occurs in the lysosomes. Clinically, ML II and ML III exhibit quite similar manifestations to mucopolysaccharidoses (MPSs), including specific skeletal deformities known as dysostosis multiplex and gingival hyperplasia. The life expectancy is less than 10 years in the severe type, and there is no definitive treatment for this disease. In this review, we have described the updated diagnosis and therapy on ML II/III.

Keywords: I-cell disease; glycosaminoglycans; inclusion body; lysosomal storage disorders; lysosome enzyme transport; mannose 6-phosphate.

Figure 1

Clinical feature of I-cell disease (kindly provided by Dr. Tadao Orii). We have signed the inform consent (A). A full-body image of the patient with I-Cell disease (a 13-month-old boy). The patient has a distinct coarse face, short neck, umbilical hernia, thick skin, and rigidity of joints. (B). The vertebral side image of a patient with I-cell disease (a 9-month-old boy). Anteroposterior diameter of the vertebral body and ossification of the anterior upper border of the lumbar vertebral body are reduced. Dysfunction is observed and hump-back of the vertebral L2 body. (C). Peripheral blood lymphocytes (at 40× magnification) of I-cell disease (mucolipidosis II) (May-Giemsa staining). The cytoplasm is filled with numerous vacuoles.

Figure 2

Stepwise modification of N-linked carbohydrate chain on lysosomal hydrolases. GlcNAc-1-phosphotransferase phosphorylates selected mannose residue on lysosomal enzymes, followed by the removal of GlcNAc from lysosomal enzymes by the uncovering enzyme. The phosphorylated enzymes bind with the mannose 6-phosphate (M6P) receptor and are internalized to the endosome and finally to the lysosomes.

Figure 3

Comparison of cell function between healthy control and ML II/III patients, adapted from Velho et al. [10]. The healthy cells phosphorylate lysosomal hydrolases by GlcNAc-1-phosphotransferase in the cis-Golgi network. The uncovering enzyme removes the masking of GlcNAc to expose M6P residues in the trans-Golgi network. The M6P-exposed enzymes are taken by endosomes with the M6P receptor and are delivered to lysosomes. In ML II/III cells, defective GlcNAc-1-phosphotransferase is unable to phosphorylate lysosomal hydrolases in the cis-Golgi network, which are targeted to the ECM, resulting in accumulation of storage materials in the lysosomes.

Figure 4

Structure of GlcNAc-1-phosphotransferase in Golgi. Adapted from Velho et al. (2019) [10]. GlcNAc-1-phosphotransferase comprises the α₂β₂γ₂ heterohexameric transmembrane protein. The site-1 protease cleaves inactive precursor protein and releases catalytically active α and β subunits.