Alternative titles; symbols
HGNC Approved Gene Symbol: AGA
SNOMEDCT: 54954004; ICD10CM: E77.1;
Cytogenetic location: 4q34.3 Genomic coordinates (GRCh38) : 4:177,430,774-177,442,437 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q34.3 | Aspartylglucosaminuria | 208400 | Autosomal recessive | 3 |
Aspartylglucosaminidase (AGA; EC 3.5.1.26) is a key enzyme in the catabolism of N-linked oligosaccharides of glycoproteins. It cleaves the asparagine from the residual N-acetylglucosamines as one of the final steps in the lysosomal breakdown of glycoproteins (summary by Ikonen et al., 1991).
Fisher et al. (1990) cloned and sequenced a cDNA for the enzyme deficient in this disorder, which they referred to as glycosylasparaginase. Tollersrud and Aronson (1989) purified glycosylasparaginase to homogeneity from rat liver and found it to have a native molecular mass of 49 kD and to comprise 2 subunits of 24 and 20 kD. From study of a cDNA for the human enzyme, Fisher et al. (1990) found that it is encoded as a 34.6-kD polypeptide that is posttranslationally processed to generate 2 subunits of approximately 19.5 (the alpha subunit) and 15 (the beta subunit) kD. The AGA cDNA encodes a deduced 436-amino acid protein.
Ikonen et al. (1991) cloned and sequenced a full-length cDNA for human AGA and studied its transient expression in COS-1 cells.
Oinonen et al. (1995) determined the high resolution crystal structure of human lysosomal aspartylglucosaminidase. The enzyme is synthesized as a single polypeptide precursor that is immediately posttranslationally cleaved into alpha- and beta-subunits. Two alpha- and beta-chains were found to pack together forming the final heterotetrameric structure. The catalytically essential residue, the N-terminal threonine of the beta-chain, is situated in the deep pocket of the funnel-shaped active site. On the basis of the structure of the enzyme-product complex, Oinonen et al. (1995) presented a catalytic mechanism for this lysosomal enzyme with an exceptionally high pH optimum. The 3-dimensional structure also allowed the prediction of the structural consequences of human mutations resulting in aspartylglucosaminuria.
By analysis of somatic cell hybrids, Aula et al. (1984) assigned the structural gene for aspartylglucosaminidase to chromosome 4q21-qter. Halal et al. (1991) presented observations they interpreted as indicating a narrowing of the assignment of the gene to 4q23-q27: a girl with a de novo direct tandem duplication of 4q23-q27 had increased activity of AGA enzyme in cultured fibroblasts. Morris et al. (1992) concluded from in situ hybridization studies that the localization is 4q32-q33. Engelen et al. (1992) found reduced activity of the enzyme in a patient with deletion of 4q33-qter.
Tenhunen et al. (1995) found that the Aga gene in the mouse is located in the central area of the B region of chromosome 8 in the region that shows homology of synteny to the telomeric region of human 4q. The mouse gene spans an 11-kb genomic region and contains 9 exons, which is analogous to the human gene. Furthermore, the exon/intron boundaries of the mouse and human genes are identically positioned.
In Finnish patients with aspartylglucosaminuria (AGU; 208400), Ikonen et al. (1991) and Fisher et al. (1991) independently identified homozygosity for a cys163-to-ser (C163S; 613228.0001) mutation in the AGA gene. The C163S mutation is responsible for 98% of the cases of AGU in Finland (Isoniemi et al., 1995).
Ikonen et al. (1991) described the spectrum of 10 AGA mutations found in 12 unrelated patients of non-Finnish origin with AGU. Since 11 of the 12 were homozygotes, consanguinity appeared to be a common denominator in most AGU families, although consanguinity could be confirmed in only 2 of the families. Screening for the unknown gene defects was done using single-strand conformation polymorphism (SSCP) analysis. The mutations were distributed over the entire coding region of the AGA cDNA, except in the carboxyl-terminal 17-kD subunit in which they were clustered within a 46-amino acid region. Based on the character of the mutations, Ikonen et al. (1991) concluded that most of the mutations probably affected the folding and stability of the molecule and did not directly affect the active site of the enzyme. There were 3 non-Finnish patients who had the 'Finnish' C163S mutation but 2 of them were Norwegian and 1 was Swedish. These patients presumably had Finnish ancestry (Borud and Torp, 1976).
Tollersrud et al. (1994) reported 9 patients from 7 families identified in northern Norway. All were homozygous for the most prevalent Finnish mutation, cys163-to-ser. Genealogic investigation of 9 parents proved Finnish ancestry in all pedigrees. These Finnish immigrants originated in the main from the Tornio valley in northern Finland in a continuous immigration movement from 1700 to 1900.
Ikonen and Peltonen (1992) reviewed a total of 11 AGA mutations published to that time.
Laitinen et al. (1997) demonstrated that 2 Canadian sibs of non-Finnish extraction had AGU on the basis of compound heterozygosity at the AGA locus: a 299G-A transition caused a gly100-to-glu substitution and a 404T-C transition caused a phe135-to-ser substitution in the enzyme.
Isoniemi et al. (1995) found 7 Finnish AGU patients to be compound heterozygotes for the C163S mutation and another mutation, namely a 2-bp deletion in the second exon of the AGA cDNA, causing a shift of the reading frame and a premature termination of the polypeptide chain.
Saarela et al. (2001) used the 3-dimensional structure of AGA to predict structural consequences of AGU mutations, including 6 novel mutations, and to characterize the effect of mutations on intracellular stability, maturation, transport, and the activity of AGA. Most mutations are substitutions replacing the original amino acid with a bulkier residue. Mutations of the dimer interface prevent dimerization in the endoplasmic reticulum, whereas active site mutations not only destroy the activity but also affect maturation of the precursor. Depending on their effects on the stability of the AGA polypeptide, the authors categorized mutations as mild, moderate, or severe.
By direct sequencing of PCR-amplified AGA cDNA from a patient with aspartylglucosaminuria (AGU; 208400), Ikonen et al. (1991) found a G-to-C mutation resulting in the substitution of serine for cysteine-163 (C163S). This mutation was found in all of 20 analyzed Finnish AGU patients, and in heterozygous form in all 53 carriers, and in none of 67 control individuals. The mutation produces a change in the predicted flexibility of the AGA polypeptide chain and removes an intramolecular S-S bridge.
Fisher et al. (1991) independently found the G-to-C transversion in DNA from Finnish AGU fibroblasts; however, they found a second G-to-A transition that resulted in an arginine-to-glutamine substitution as well. The 2 substitutions were present in all 3 Finnish cases studied and in none of 2 non-Finnish AGU fibroblast lines. In non-Finnish AGU fibroblasts, Fisher et al. (1991) found deletions as the apparent cause of the AGA deficiency. Mononen et al. (1991) likewise found 2 mutations, R161Q and C163S. Both mutations resulted in novel restriction endonuclease sites and were present in all 8 Finnish AGU patients studied, but they were absent from Finnish and non-Finnish controls and a non-Finnish case of AGU. Both amino acid changes would be expected to modify the structure of the protein profoundly: the replacement of an arginine by glutamine represents the substitution of a basic amino acid for one containing an uncharged polar group; the replacement of cysteine by serine may abolish a disulfide bridge. Whether both mutations are involved in the pathologic consequences or whether one mutation is a polymorphism was uncertain.
Ikonen et al. (1991) showed by in vitro mutagenesis studies that the C163S mutation is responsible for enzyme deficiency, whereas the arg161-to-gln (R161Q) substitution, which accompanies the other mutation in 98% of AGU alleles in Finland, represents a rare polymorphism. Cysteine-163 was shown to participate in an S-S bridge. The absence of this covalent crosslink in the mutated protein probably results in disturbed folding of the polypeptide chain and consequent decrease in its intracellular stability. Fisher and Aronson (1991) likewise found the 482G-A transition and the 488G-C transversion and demonstrated that only the latter was responsible for deficiency of glycosylasparaginase activity. The substitution prevented the normal posttranslational processing of the precursor polypeptide into its alpha and beta subunits.
The C163S mutation is responsible for 98% of the cases of AGU in Finland (Isoniemi et al., 1995).
In a 10-year-old Turkish child with aspartylglucosaminuria (AGU; 208400), Ikonen et al. (1991) found a G-to-A substitution at nucleotide 904 of the AGA gene, resulting in substitution of arginine for glycine-302 (G302R). The patient was homozygous for the mutation and showed fibroblast AGA activity about 7% of normal. The parents were first cousins.
In a 16-year-old white American patient with aspartylglucosaminuria (AGU; 208400), Ikonen et al. (1991) found by the SSCP method a T-to-C change at nucleotide 916 of the AGA gene, resulting in substitution of arginine for cysteine-306 (C306R).
In a 3-year-old German child with aspartylglucosaminuria (AGU; 208400), previously reported by Ziegler et al. (1989), Ikonen et al. (1991) found a G-to-A substitution at nucleotide 179 of the AGA gene, resulting in substitution of the negatively charged aspartic acid for uncharged glycine at residue 60 (G60D).
In a 1-year-old Italian child with aspartylglucosaminuria (AGU; 208400), Ikonen et al. (1991) found a C-to-T transition at nucleotide 302 of the AGA gene, resulting in a change changed alanine-101 to valine (A101V). The patient was homozygous for this mutation, which was discovered by the SSCP method. The same mutation was found in a compound heterozygous state in an English patient (see 613228.0006).
In a 5-year-old English child with aspartylglucosaminuria (AGU; 208400), Ikonen et al. (1991) found compound heterozygosity for the A101V mutation (613228.0005) and a 7-nucleotide deletion (102_108delfs34Ter) in the AGA gene. The gene deletion would be predicted to result in the formation of a truncated polypeptide chain of only 33 amino acids.
In a 17-year-old Spanish American patient with aspartylglucosaminuria (AGU; 208400), Ikonen et al. (1991) found insertion of a single thymidine after nucleotide 800 in the AGA gene, resulting in a shift in the reading frame and a premature stop codon causing a truncated polypeptide chain with 318 amino acids of which the first 267 amino acids represented the normal AGA polypeptide (800_801insfs319Ter).
In a 3-year-old Tunisian child with aspartylglucosaminuria (AGU; 208400), the offspring of first-cousin parents, Ikonen et al. (1991) found homozygosity for a 6-nucleotide insertion (ATGCGG) after nucleotide 127 in the AGA gene, causing an in-frame insertion of aspartic acid and alanine after amino acid 42.
In a 12-year-old black American patient with aspartylglucosaminuria (AGU; 208400) (Hreidarsson et al., 1983; Camden number GM03560), Ikonen et al. (1991) found homozygosity for a deletion of nucleotides 807-940 in the AGA gene. Further sequence analysis of both cDNA and genomic DNA confirmed that a 134-bp exon was missing from the cDNA and that a G-to-T substitution had occurred in the adjacent 3-prime intron at position +1 of the splice donor site; the authors thus concluded that this was a splicing mutation. The mutation resulted in a transcript that was 134-bp shorter than normal. The mutation also resulted in the shift of the reading frame and a premature termination codon at the beginning of the following exon.
In an 8-year-old Dutch child with aspartylglucosaminuria (AGU; 208400), Ikonen et al. (1991) found deletion of 1 nucleotide, thymidine-336, in the AGA gene. This resulted in a frameshift and premature termination of the polypeptide chain after 126 amino acids.
Peltola et al. (1996) reported that a T-to-C change at codon 214 in the AGA gene, leading to a ser72-to-pro (S72P) substitution, occurred in affected members of 4 Arab families with aspartylglucosaminuria (AGU; 208400). They noted that this mutation is the first naturally occurring AGA mutation that involves an active site and is apparently the second most common AGA mutation worldwide.
Aula, P., Astrin, K. H., Francke, U., Desnick, R. J. Assignment of the structural gene encoding human aspartylglucosaminidase to the long arm of chromosome 4 (4q21-4qter). Am. J. Hum. Genet. 36: 1215-1224, 1984. [PubMed: 6517050]
Aula, P., Astrin, K. H., Francke, U., Desnick, R. J. Assignment of the structural gene encoding human aspartylglucosaminidase to the long arm of chromosome 4 (4q21-4qter). (Abstract) Am. J. Hum. Genet. 36: 201S only, 1984.
Aula, P., Rapola, J., von Koskull, H., Ammala, P. Prenatal diagnosis and fetal pathology of aspartylglucosaminuria. Am. J. Med. Genet. 19: 359-367, 1984. [PubMed: 6507482] [Full Text: https://doi.org/10.1002/ajmg.1320190218]
Borud, O., Torp, K. H. Aspartylglycosaminuria in northern Norway (Letter) Lancet 307: 1082-1083, 1976. Note: Originally Volume I. [PubMed: 57494] [Full Text: https://doi.org/10.1016/s0140-6736(76)92266-2]
Engelen, J., Hamers, A., Schrander-Stumpel, C., Mulder, H., Poorthuis, B. Assignment of the aspartylglucosaminidase gene (AGA) to 4q33-q35 based on decreased activity in a girl with a 46,XX,del(4)(q33) karyotype. Cytogenet. Cell Genet. 60: 208-209, 1992. [PubMed: 1505217] [Full Text: https://doi.org/10.1159/000133338]
Fisher, K. J., Aronson, N. N., Jr. Characterization of the mutation responsible for aspartylglucosaminuria in three Finnish patients: amino acid substitution cys163-to-ser abolishes the activity of lysosomal glycosylasparaginase and its conversion into subunits. J. Biol. Chem. 266: 12105-12113, 1991. [PubMed: 1904874]
Fisher, K. J., Tollersrud, O. K., Aronson, N. N., Jr. Cloning and sequence analysis of a cDNA for human glycosylasparaginase: a single gene encodes the subunits of this lysosomal amidase. FEBS Lett. 269: 440-444, 1990. Note: Erratum. FEBS Lett. 276: 232 only, 1990. [PubMed: 2401370] [Full Text: https://doi.org/10.1016/0014-5793(90)81211-6]
Fisher, K. J., Tollersrud, O. K., Aronson, N. N., Jr. Molecular genetics of aspartylglucosaminuria. (Abstract) Nucleic Acids Res. Symp. 23: 8 only, 1991.
Halal, F., Vekemans, M., Chitayat, D. Interstitial tandem direct duplication of the long arm of chromosome 4 (q23-q27) and possible assignment of the structural gene encoding human aspartylglucosaminidase to this segment. Am. J. Med. Genet. 39: 418-421, 1991. [PubMed: 1877620] [Full Text: https://doi.org/10.1002/ajmg.1320390412]
Hreidarsson, S., Thomas, G. H., Valle, D. L., Stevenson, R. E., Taylor, H., McCarty, J., Coker, S. B., Green, W. R. Aspartylglucosaminuria in the United States. Clin. Genet. 23: 427-435, 1983. [PubMed: 6883788] [Full Text: https://doi.org/10.1111/j.1399-0004.1983.tb01977.x]
Ikonen, E., Aula, P., Gron, K., Tollersrud, O., Halila, R., Manninen, T., Syvanen, A.-C., Peltonen, L. Spectrum of mutations in aspartylglucosaminuria. Proc. Nat. Acad. Sci. 88: 11222-11226, 1991. [PubMed: 1722323] [Full Text: https://doi.org/10.1073/pnas.88.24.11222]
Ikonen, E., Baumann, M., Gron, K., Syvanen, A.-C., Enomaa, N., Halila, R., Aula, P., Peltonen, L. Aspartylglucosaminuria: cDNA encoding human aspartylglucosaminidase and the missense mutation causing the disease. EMBO J. 10: 51-58, 1991. [PubMed: 1703489] [Full Text: https://doi.org/10.1002/j.1460-2075.1991.tb07920.x]
Ikonen, E., Enomaa, N., Ulmanen, I., Peltonen, L. In vitro mutagenesis helps to unravel the biological consequences of aspartylglucosaminuria mutation. Genomics 11: 206-211, 1991. [PubMed: 1765378] [Full Text: https://doi.org/10.1016/0888-7543(91)90120-4]
Ikonen, E., Peltonen, L. Mutations causing aspartylglucosaminuria (AGU): a lysosomal accumulation disease. Hum. Mutat. 1: 361-365, 1992. [PubMed: 1301945] [Full Text: https://doi.org/10.1002/humu.1380010503]
Isoniemi, A., Hietala, M., Aula, P., Jalanko, A., Peltonen, L. Identification of a novel mutation causing aspartylglucosaminuria reveals a mutation hotspot region in the aspartylglucosaminidase gene. Hum. Mutat. 5: 318-326, 1995. [PubMed: 7627186] [Full Text: https://doi.org/10.1002/humu.1380050408]
Laitinen, A., Hietala, M., Haworth, J. C., Schroeder, M. L., Seargeant, L. E., Greenberg, C. R., Aula, P. Two novel mutations in a Canadian family with aspartylglucosaminuria and early outcome post bone marrow transplantation. Clin. Genet. 51: 174-178, 1997. [PubMed: 9137882] [Full Text: https://doi.org/10.1111/j.1399-0004.1997.tb02448.x]
Mononen, I., Fisher, K. J., Kaartinen, V., Aronson, N. N., Jr. Aspartylglycosaminuria: protein chemistry and molecular biology of the most common lysosomal storage disorder of glycoprotein degradation. FASEB J. 7: 1247-1256, 1993. [PubMed: 8405810] [Full Text: https://doi.org/10.1096/fasebj.7.13.8405810]
Mononen, I., Heisterkamp, N., Kaartinen, V., Mononen, T., Williams, J. C., Groffen, J. Aspartylglycosaminuria in a non-Finnish patient caused by a donor splice mutation in the glycoasparaginase gene. J. Biol. Chem. 267: 3196-3199, 1992. [PubMed: 1737774]
Mononen, I., Heisterkamp, N., Kaartinen, V., Williams, J. C., Yates, J. R., III, Griffin, P. R., Hood, L. E., Groffen, J. Aspartylglycosaminuria in the Finnish population: identification of two point mutations in the heavy chain of glycoasparaginase. Proc. Nat. Acad. Sci. 88: 2941-2945, 1991. [PubMed: 2011603] [Full Text: https://doi.org/10.1073/pnas.88.7.2941]
Morris, C., Heisterkamp, N., Groffen, J., Williams, J. C., Mononen, I. Chromosomal localization of the human glycoasparaginase gene to 4q32-q33. Hum. Genet. 88: 295-297, 1992. [PubMed: 1733831] [Full Text: https://doi.org/10.1007/BF00197262]
Oinonen, C., Tikkanen, R., Rouvinen, J., Peltonen, L. Three-dimensional structure of human lysosomal aspartylglucosaminidase. Nature Struct. Biol. 2: 1102-1108, 1995. [PubMed: 8846222] [Full Text: https://doi.org/10.1038/nsb1295-1102]
Peltola, M., Tikkanen, R., Peltonen, L., Jalanko, A. Ser72pro active-site disease mutation in human lysosomal aspartylglucosaminidase: abnormal intracellular processing and evidence for extracellular activation. Hum. Molec. Genet. 5: 737-743, 1996. [PubMed: 8776587] [Full Text: https://doi.org/10.1093/hmg/5.6.737]
Saarela, J., Laine, M., Oinonen, C., von Schantz, C., Jalanko, A., Rouvinen, J., Peltonen, L. Molecular pathogenesis of a disease: structural consequences of aspartylglucosaminuria mutations. Hum. Molec. Genet. 10: 983-995, 2001. [PubMed: 11309371] [Full Text: https://doi.org/10.1093/hmg/10.9.983]
Tenhunen, K., Laan, M., Manninen, T., Palotie, A., Peltonen, L., Jalanko, A. Molecular cloning, chromosomal assignment, and expression of the mouse aspartylglucosaminidase gene. Genomics 30: 244-250, 1995. [PubMed: 8586423] [Full Text: https://doi.org/10.1006/geno.1995.9881]
Tollersrud, O. K., Aronson, N. N., Jr. Purification and characterization of rat liver glycosylasparaginase. Biochem. J. 260: 101-108, 1989. [PubMed: 2775174] [Full Text: https://doi.org/10.1042/bj2600101]
Tollersrud, O. K., Nilssen, O., Tranebjaerg, L., Borud, O. Aspartylglucosaminuria in northern Norway: a molecular and genealogical study. J. Med. Genet. 31: 360-363, 1994. [PubMed: 8064811] [Full Text: https://doi.org/10.1136/jmg.31.5.360]
Ziegler, R., Schmidt, H., Sewell, A. C., Weglage, J., v. Lengerke, J. H., Ullrich, K. Aspartylglucosaminurie: Klinische Beschreibung von zwei deutschen Patienten. Mschr. Kinderheilk. 137: 454-457, 1989. [PubMed: 2811876]