Alternative titles; symbols
HGNC Approved Gene Symbol: GNPTG
Cytogenetic location: 16p13.3 Genomic coordinates (GRCh38) : 16:1,351,931-1,364,113 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16p13.3 | Mucolipidosis III gamma | 252605 | Autosomal recessive | 3 |
UDP-N-acetylglucosamine:lysosomal-enzyme N-acetylglucosamine-1-phosphotransferase (GlcNAc-phosphotransferase; EC 2.7.8.17) catalyzes the initial step in the synthesis of the mannose 6-phosphate (M6P) determinant required for efficient intracellular targeting of newly synthesized lysosomal hydrolases to the lysosome. GlcNAc-phosphotransferase is an alpha-2/beta-2/gamma-2 hexameric complex, the enzyme product of 2 genes: the gamma subunit is encoded by the GNPTG gene on chromosome 16, and the alpha and beta subunits are encoded by the GNPTAB gene (607840) on chromosome 12.
Bao et al. (1996, 1996) determined that bovine GlcNAc-phosphotransferase is a 54-kD alpha-2/beta-2/gamma-2 hexameric complex. By EST database searching with the bovine GlcNAc-phosphotransferase gamma subunit as query, Raas-Rothschild et al. (2000) identified a partial clone of the human counterpart. They cloned a full-length GNPTAG cDNA by PCR, using a human brain cDNA library. The deduced mature GNPTAG protein has 281 amino acids and a molecular mass of 31 kD. It contains 2 N-glycosylation sites. Northern blot analysis detected a single 1.3-kb transcript in all 8 tissues examined. Additional transcripts up to 7.5 kb were found in lung.
By radiation hybrid analysis, the EST corresponding to human GNPTG had been mapped to chromosome 16. By sequence analysis, Raas-Rothschild et al. (2000) mapped the GNPTG gene to 16p.
Mucolipidosis III Gamma
By sequence analysis of the GNPTAG in patients from 3 families with mucolipidosis IIIC (252605), Raas-Rothschild et al. (2000) identified a frameshift mutation that segregated with the disease (607838.0001).
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 IIIC, Encarnacao et al. (2009) identified compound heterozygosity for 2 mutations in the GNPTG gene (607838.0007 and 607838.0008). Both the GNPTG and GNPTAB mRNA transcripts were significantly decreased (10- and 2.4-fold, respectively) compared to controls. The patient had a relatively mild phenotype with onset at age 10 years, no psychomotor retardation, and survival into adulthood. Encarnacao et al. (2009) 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.
Associations Pending Confirmation
For discussion of a possible association between variation in the GNPTG gene and persistent stuttering, see STUT2 (609261).
In 3 families segregating mucolipidosis IIIC (252605), the variant form of pseudo-Hurler polydystrophy, Raas-Rothschild et al. (2000) identified a frameshift mutation in the GNPTG gene: insertion of a single cytosine at codon 167, with a frameshift predicting a premature translation termination 107 bp downstream from the insertion.
In 2 Italian sibs with mucolipidosis IIIC (252605), Persichetti et al. (2009) identified a homozygous 1-bp deletion (611delG) in the GNPTG gene, predicted to result in a frameshift (Gly204AlafsTer6) and premature termination, leading to the synthesis of a truncated protein or nonsense-mediated mRNA decay.
In a Spanish boy with mucolipidosis IIIC (252605), Persichetti et al. (2009) identified a homozygous 28-bp deletion at (640_667del28) in the GNPTG gene, predicted to result in a frameshift and premature termination (Glu214LysfsTer37), leading to a synthesis of a truncated protein or nonsense-mediated mRNA decay.
In 2 Spanish sibs with mucolipidosis IIIC (252605), Persichetti et al. (2009) identified a homozygous 333G-A transition in the GNPTG gene, resulting in a trp111-to-ter (W111X) substitution.
In 2 Italian sibs with mucolipidosis IIIC (252605), Persichetti et al. (2009) identified compound heterozygosity for 2 mutations in the GNPTG gene: an A-to-G transition in intron 8, resulting in a splice site mutation, and 316G-A transition resulting in a gly106-to ser (G106S; 607838.0006) substitution in a highly conserved residue. Functional expression studies showed that the splice site mutation generated a transcript that skipped exon 9 and a longer transcript that retained introns 8 and 9, resulting in frameshift and a premature termination codon.
For discussion of the gly106-to-ser (G106S) mutation in the GNPTG gene that was found in compound heterozygous state in 2 sibs with mucolipidosis IIIC (252605) by Persichetti et al. (2009), see 607838.0005.
In a Portuguese patient with mucolipidosis III gamma (252605), Encarnacao et al. (2009) identified compound heterozygosity for 2 mutations in the GNPTG gene: a 1-bp deletion (639delT) resulting in a frameshift and premature termination, and a G-to-T transversion in intron 8 (610-1G-T; 607838.0008), resulting in abnormal splicing. Both the GNPTG and GNPTAB mRNA transcripts were significantly decreased (10- and 2.4-fold, respectively) compared to controls. The authors suggested that both GNPTG mutations were subject to nonsense-mediated mRNA decay. The patient had a relatively mild phenotype with onset at age 10 years, no psychomotor retardation, and survival into adulthood.
For discussion of the splice site mutation in the GNPTG gene (610-1G-T) that was found in compound heterozygous state in a patient with mucolipidosis III gamma (252605) by Encarnacao et al. (2009), see 607838.0007.
In 3 Afghan sibs with mucolipidosis III gamma (252605), Pohl et al. (2010) identified a homozygous G-to-A transition in intron 7 of the GNPTG gene, resulting in a activation of a cryptic 3-prime splice site, frameshift, and premature termination. There were reduced levels of mutant mRNA and Western blot analysis showed lack of the GNPTG protein, consistent with nonsense-mediated mRNA decay. The patients 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 sisters 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. 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 M6P-containing proteins in fibroblasts extracts.
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]
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]
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]