Alternative titles; symbols
ORPHA: 423470, 577; DO: 0080678;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 16p13.3 | Mucolipidosis III gamma | 252605 | Autosomal recessive | 3 | GNPTG | 607838 |
A number sign (#) is used with this entry because mucolipidosis III gamma is caused by homozygous or compound heterozygous mutation in the GNPTG gene (607838), which encodes the gamma subunit of N-acetylglucosamine-1-phosphotransferase, on chromosome 16p13.
Mucolipidosis II alpha/beta, or I-cell disease (252500), and mucolipidosis III alpha/beta, or pseudo-Hurler polydystrophy (252600), are related disorders caused by mutations in the GNPTAB gene (607840), encoding the alpha and beta subunits of the N-acetylglucosamine-1-phosphotransferase.
Mucolipidosis type III gamma is an autosomal recessive disorder characterized clinically by short stature, skeletal abnormalities, cardiomegaly, and developmental delay. The disorder is caused by a defect in proper lysosomal enzyme phosphorylation and localization, which results in accumulation of lysosomal substrates (summary by Raas-Rothschild et al., 2000).
Cathey et al. (2008) reported an updated nomenclature classification system for mucolipidosis II and III. ML II was renamed ML II alpha/beta; ML IIIA was renamed ML III alpha/beta; and ML IIIC was renamed ML III gamma.
Encarnacao et al. (2009) reported a Portuguese patient with mucolipidosis III gamma. He had a relatively mild phenotype with onset at age 10 years, no psychomotor retardation, and survival into adulthood.
Pohl et al. (2010) reported 2 Afghan sisters and a brother, born of consanguineous parents, with mucolipidosis III gamma. All presented at about 7 years of age with progressive joint pain and stiffness, especially affecting the fingers, hip, and spine. All had myopia, but hearing and intelligence were normal. The 2 girls had short stature, but their brother had normal height. Physical examination of all 3 sibs as teenagers showed short neck, hyperlordosis of the spine, short trunks, genu valgum, flat feet, and reduced joint mobility and contractures of the shoulders, spine, and fingers. Radiographs showed signs of spondyloepiphyseal dysplasia. Cultured fibroblasts derived from the brother showed reduced activities (30 to 50%) of lysosomal enzymes compared to controls. Radiolabeling of the lysosomal enzyme cathepsin D showed that patient fibroblasts had decreased levels of newly synthesized protein, and that most (70%) of the newly synthesized protein was missorted into the medium and not targeted to lysosomes. There were also low levels of mannose-6-phosphate (M6P)-containing proteins in fibroblasts extracts. Genetic analysis identified a homozygous mutation in the GNPTG gene (607838.0009).
Complementation studies by Shows and coworkers (Honey et al., 1982; Shows et al., 1982; Mueller et al., 1983) indicated the presence of a single complementation group in mucolipidosis II (252500) and 3 distinct complementation groups among patients with mucolipidosis III. Complementation group A was identical with mucolipidosis II, i.e., there was no complementation of cell lines; complementation group B consisted of a single cell line; and complementation group C included the variant form described by Varki et al. (1981). The mutant enzymes on the 2 major complementation groups, A and C, differed from each other by the optimum temperature of enzymic activity (Little et al., 1986), by the susceptibility of the phosphorylation of mono- and oligosaccharide acceptors to inhibition by lysosomal enzyme preparations, and by their apparent molecular sizes. Ben-Yoseph et al. (1992) found that cultured skin fibroblasts from ML II and III patients who were designated as variants (1 of 4 ML II and 3 of 6 ML III patients) showed normal N-acetylglucosamine 1-phosphotransferase activity toward mono- and oligosaccharide acceptor substrates. Contrariwise, the activity toward natural lysosomal protein acceptors was absent or deficient in cell preparations from all patients with classic as well as variant forms of the 2 disorders. Complementation analysis showed that, while cell lines with variant ML III constituted a complementation group distinct from that of the classic forms of ML II and III, the variant ML II cell line belonged to the same complementation group as did the classic forms. In contrast to the mutant enzyme from variant ML III patients, which failed to recognize lysosomal proteins as the specific acceptor substrates, the activity toward alpha-methylmannoside in the variant ML II patient could be inhibited by exogenous lysosomal enzyme preparations. Ben-Yoseph et al. (1992) interpreted these findings as indicating that N-acetylglucosamine-1-phosphotransferase is composed of at least 2 distinct polypeptides: a recognition subunit that is defective in the ML III variant and a catalytic subunit that is deficient or altered in the classic forms of ML II and III as well as in the ML II variant. Bao et al. (1996, 1996) determined that bovine GNPTA is an alpha-2/beta-2/gamma-2 hexameric complex.
In a large Druze family in which multiple members had ML IIIC, Raas-Rothschild et al. (2000) demonstrated linkage of the disorder to chromosome 16p13.3.
By sequence analysis, Raas-Rothschild et al. (2000) identified a frameshift mutation in the GNPTG gene (607838.0001) in affected members of 3 families with ML IIIC. Raas-Rothschild et al. (2000) suggested that the gamma subunit functions in lysosomal hydrolase recognition.
In 10 patients from 7 families with mucolipidosis IIIC, Persichetti et al. (2009) identified 6 novel mutations in the GNPTG gene (see, e.g., 607838.0002-607838.0006).
In a Portuguese patient with mucolipidosis III gamma, Encarnacao et al. (2009) identified compound heterozygosity for 2 mutations in the GNPTG gene (607838.0007 and 607838.0008). Both GNPTG and GNPTAB mRNA transcripts were significantly decreased (10- and 2.4-fold, respectively) compared to controls. The authors suggested that the relatively mild phenotype could probably be explained by the fact that the gamma subunit does not contribute to the catalytic function of the enzyme.
Bao, M., Booth, J. L., Elmendorf, B. J., Canfield, W. M. Bovine UDP-N-acetylglucosamine:lysosomal-enzyme N-acetylglucosamine-1-phosphotransferase: I. Purification and subunit structure. J. Biol. Chem. 271: 31437-31445, 1996. [PubMed: 8940155] [Full Text: https://doi.org/10.1074/jbc.271.49.31437]
Bao, M., Elmendorf, B. J., Booth, J. L., Drake, R. R., Canfield, W. M. Bovine UDP-N-acetylglucosamine:lysosomal-enzyme N-acetylglucosamine-1-phosphotransferase: II. Enzymatic characterization and identification of the catalytic subunit. J. Biol. Chem. 271: 31446-31451, 1996. [PubMed: 8940156] [Full Text: https://doi.org/10.1074/jbc.271.49.31446]
Ben-Yoseph, Y., Mitchell, D. A., Yager, R. M., Wei, J. T., Chen, T.-H., Shih, L. Y. Mucolipidoses II and III variants with normal N-acetylglucosamine 1-phosphotransferase activity toward alpha-methylmannoside are due to nonallelic mutations. Am. J. Hum. Genet. 50: 137-144, 1992. [PubMed: 1309624]
Cathey, S. S., Kudo, M., Tiede, S., Raas-Rothschild, A., Braulke, T., Beck, M., Taylor, H. A., Canfield, W. M., Leroy, J. G., Neufeld, E. F., McKusick, V. A. Molecular order of mucolipidosis II and III nomenclature. (Letter) Am. J. Med. Genet. 146A: 512-513, 2008. [PubMed: 18203164] [Full Text: https://doi.org/10.1002/ajmg.a.32193]
Encarnacao, M., Lacerda, L., Costa, R., Prata, M. J., Coutinho, M. F., Ribeiro, H., Lopes, L., Pineda, M., Ignatius, J., Galvez, H., Mustonen, A., Vieira, P., Lima, M. R., Alves, S. Molecular analysis of the GNPTAB and GNPTG genes in 13 patients with mucolipidosis type II or type III - identification of eight novel mutations. Clin. Genet. 76: 76-84, 2009. [PubMed: 19659762] [Full Text: https://doi.org/10.1111/j.1399-0004.2009.01185.x]
Honey, N. K., Mueller, O. T., Little, L. E., Miller, A. L., Shows, T. B. Mucolipidosis III is genetically heterogeneous. Proc. Nat. Acad. Sci. 79: 7420-7424, 1982. [PubMed: 6961420] [Full Text: https://doi.org/10.1073/pnas.79.23.7420]
Little, L. E., Mueller, O. T., Honey, N. K., Shows, T. B., Miller, A. L. Heterogeneity of N-acetylglucosamine 1-phosphotransferase within mucolipidosis III. J. Biol. Chem. 261: 733-738, 1986. [PubMed: 3001079]
Mueller, O. T., Honey, N. K., Little, L. E., Miller, A. L., Shows, T. B. Mucolipidosis II and III: the genetic relationships between two disorders of lysosomal enzyme biosynthesis. J. Clin. Invest. 72: 1016-1023, 1983. [PubMed: 6309902] [Full Text: https://doi.org/10.1172/JCI111025]
Persichetti, E., Chuzhanova, N. A., Dardis, A., Tappino, B., Pohl, S., Thomas, N. S. T., Rosano, C., Balducci, C., Paciotti, S., Dominissini, S., Montalvo, A. L., Sibilio, M., and 9 others. Identification and molecular characterization of six novel mutations in the UDP-N-acetylglucosamine-1-phosphotransferase gamma subunit (GNPTG) gene in patients with mucolipidosis III gamma. Hum. Mutat. 30: 978-984, 2009. [PubMed: 19370764] [Full Text: https://doi.org/10.1002/humu.20959]
Pohl, S., Encarnacao, M., Castrichini, M., Muller-Loennies, S., Muschol, N., Braulke, T. Loss of N-acetylglucosamine-1-phosphotransferase gamma subunit due to intronic mutation in GNPTG causes mucolipidosis type III gamma: implications for molecular and cellular diagnostics. Am. J. Med. Genet. 152A: 124-132, 2010. [PubMed: 20034096] [Full Text: https://doi.org/10.1002/ajmg.a.33170]
Raas-Rothschild, A., Cormier-Daire, V., Bao, M., Genin, E., Salomon, R., Brewer, K., Zeigler, M., Mandel, H., Toth, S., Roe, B., Munnich, A., Canfield, W. M. Molecular basis of variant pseudo-Hurler polydystrophy (mucolipidosis IIIC). J. Clin. Invest. 105: 673-681, 2000. [PubMed: 10712439] [Full Text: https://doi.org/10.1172/JCI5826]
Shows, T. B., Mueller, O. T., Honey, N. K., Wright, C. E., Miller, A. L. Genetic heterogeneity of I-cell disease is demonstrated by complementation of lysosomal enzyme processing mutants. Am. J. Med. Genet. 12: 343-353, 1982. [PubMed: 6287841] [Full Text: https://doi.org/10.1002/ajmg.1320120312]
Varki, A. P., Reitman, M. L., Kornfeld, S. Identification of a variant of mucolipidosis III (pseudo Hurler polydystrophy): a catalytically active N-acetylglucosaminylphosphotransferase that fails to phosphorylate lysosomal enzymes. Proc. Nat. Acad. Sci. 78: 7773-7777, 1981. [PubMed: 6461005] [Full Text: https://doi.org/10.1073/pnas.78.12.7773]