+208400	GeneTests, Links
ASPARTYLGLUCOSAMINURIA

Alternative titles; symbols

AGU
GLYCOSYLASPARAGINASE DEFICIENCY
ASPARTYLGLUCOSAMINIDASE DEFICIENCY
AGA DEFICIENCY
GLYCOASPARAGINASE
ASPARTYLGLYCOSAMINURIA
ASPARTYLGLUCOSAMINIDASE, INCLUDED; AGA, INCLUDED

Gene map locus 4q32-q33

TEXT

Aspartylglucosaminuria is a lysosomal disease caused by deficiency of N-aspartyl-beta-glucosaminidase. It was first reported by Jenner and Pollitt (1967) and Pollitt et al. (1968), who found urinary excretion of abnormal amounts of 2-acetamido-1-(beta-L-aspartamido)-1,2-dideoxyglucose in a 32-year-old female and her 20-year-old brother with mental retardation. An enzyme responsible for hydrolyzing this compound is normally present in seminal fluid but was absent in that of the brother. A generalized lack of this enzyme was postulated. Both sibs had thick sagging skin of the cheeks, a finding not present in normal members of the family. Palo and Mattsson (1970) reported 11 cases. The parents of 1 patient were first cousins. They estimated that there are at least 130 cases in the total population of 4.5 million in Finland. The Finnish cases showed, in addition to severe mental retardation, sagging cheeks, broad nose and face, short neck, cranial asymmetry, scoliosis, periodic hyperactivity, and vacuolated lymphocytes. Diarrhea and frequent infections were problems in infancy. PKU (261600) has a very low incidence in Finland (Palo, 1967); AGU is in Finland what PKU is in many other populations. Aspartylglucosaminuria has also been observed in Finns living in Norway (Borud and Torp, 1976). Autio (1980) estimated the frequency at 1 in 26,000 in Finland. A total of 128 cases in 97 families had been identified. Mononen et al. (1991) found a frequency of 1 in 3,643 in a study of children in eastern Finland. This frequency is consistent with a carrier rate of 1 in 30 and indicates that this disorder, after trisomy 21 and the fragile X syndrome, is the most common genetic cause of mental retardation.

The disorder reported by Fountain (1974) was shown not to be aspartylglucosaminuria despite similarities (Fountain, 1977). Indeed, that disorder appears to represent a distinct autosomal recessive disorder (see Fountain syndrome, 229120). Gehler et al. (1981) described affected brother and sister in a consanguineous Italian sibship; one of the patients showed angiokeratoma corporis diffusum. Yoshida et al. (1991) and Vargas-Diez et al. (2002) also described the occurrence of angiokeratoma corporis diffusum in 2 Japanese patients and 1 Spanish patient, respectively, with aspartylglucosaminuria. Stevenson et al. (1982) reported this disorder in an 18-year-old American. The family name was Scottish-Irish. The mother was said to have been aged 13 years and the father was unknown--circumstances suggesting incest. Mental retardation, recurrent infections, cardiomyopathy, and emotional lability were features. Hreidarsson et al. (1983) reported a case in an American black and an American white of uncertain parentage. Radiographic changes in the hands were noted: thin epiphyses, broad 'poorly modeled' (undertubulated) metacarpals, and peculiarly shaped carpal bones. Isenberg and Sharp (1975) reported the case of a girl of Mexican-Italian extraction living in the U.S. Musumeci et al. (1984) reported a child with both enzymopathic methemoglobinemia (250800) and AGU. Since the structural genes for the enzymes deficient in these 2 disorders are on separate chromosomes, a single mutation such as a small deletion is not likely to be the basis. Furthermore, a sib had only AGU. The parents were consanguineous. Chitayat et al. (1988) described 3 Puerto Rican brothers, with first-cousin parents, who had AGU. Two of the brothers were monozygotic twins. Macroorchidism became evident in all 3 boys at the time of puberty. This feature had not previously been noted in AGU, although other endocrinologic abnormalities had been described. Yoshida et al. (1991) described the first Japanese patients with AGU--a brother and sister, aged 45 and 41, respectively. Both sibs had mental retardation, coarse facial features, angiokeratoma, and myoclonic seizures.

Gordon et al. (1998) described a Canadian family in which 4 of 12 sibs were affected, 2 brothers and 2 sisters. Though apparently normal at birth, their developmental milestones, particularly speech, were slow, and they acquired only a simple vocabulary. There was a progressive coarsening of facial features; 3 had inguinal hernia and recurrent diarrhea; all became severely retarded and by the fourth decade showed evident deterioration of both cognitive and motor skills; and 2 exhibited cyclic behavioral changes. Three of the sibs had died, at 33, 39, and 44 years of age.

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. The enzyme is also known as glycoasparaginase. AGU is the only known lysosomal storage disease caused by an amidase deficiency. 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. Ikonen et al. (1991) cloned and sequenced a full-length cDNA for human AGA and studied its transient expression in COS-1 cells.

By analysis of somatic cell hybrids, Aula et al. (1984) assigned the structural gene for aspartylglucosaminidase to 4q21-qter. In 12 AGU families with 15 affected persons and 50 carriers (determined by reduced activity of enzyme in lymphocytes), Gron et al. (1989, 1990) studied linkage to chromosome 4 markers and concluded that the locus is distal to MNS (111300). They suggested the order cen--ADH--EGF--FG--MNS--AGU. 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.

Ikonen et al. (1991) described the spectrum of 10 AGU mutations found in 12 unrelated patients of non-Finnish origin. Since 11 of the 12 were homozygotes, consanguinity appears 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 AGU 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' cys163-to-ser mutation (208400.0001) 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 on 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 AGU mutations published to that time.

Mononen et al. (1994) described a fluorometric glycosylasparaginase assay for neonatal screening for AGU.

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.

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.

The cys163-to-ser (C163S) mutation is responsible for 98% of the cases of AGU in Finland. 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.

Zlotogora et al. (1997) diagnosed this disorder in 8 patients originating from 3 unrelated families, all Palestinian Arabs from the region of Jerusalem. They found the clinical diagnosis of AGU to be often difficult, in particular early in the course of the disease, and most of the patients were diagnosed after the age of 5 years. On the other hand, since these patients excrete early large amounts of aspartylglucosamine in urine, biochemical detection is easy by urine chromatography.

Arvio et al. (1999) studied 66 Finnish patients with AGU for changes in the oral mucosa and 44 of those for changes in facial skin. Nine patients had facial angiofibromas. Edema of the buccal mucosa and gingival overgrowths were more frequent in AGU patients than in controls (P less than 0.001). Of 16 oral mucosal lesions studied histologically, 15 represented fibroepithelial or epithelial hyperplasias. Cytoplasmic vacuolization was evident in only 4. Expression of AGA in mucosal lesions of AGU patients did not differ from that seen in corresponding lesions of normal subjects.

Arvio et al. (2001) described the state of health, intellectual skills, and dysmorphic features of 19 young patients with aspartylglucosaminuria. Of the 19, 5 had undergone a successful bone marrow transplantation between 1991 and 1997. The first 2 patients who received transplants were, after 7 and 5 years' follow-up, more severely mentally retarded than the nontransplanted patients. The general health of the latter group was quite good, whereas the 5 patients who underwent bone marrow transplantation had posttransplant complications. Arvio et al. (2001) concluded that bone marrow transplantation should not be encouraged for the treatment of patients with aspartylglucosaminuria after infancy.

Nomenclature: Some early publications (Autio et al., 1974; Borud and Torp, 1976; 16,17:Gehler et al., 1981, 1981; Maury, 1980), as well as some recent authors (Kaartinen et al., 1996; Mononen et al., 1994), used the designation aspartylglycosaminuria. Aspartylglucosaminuria appears to be the most widely used designation.

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.

ANIMAL MODEL

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 and 8 introns, which is analogous to the human gene. Furthermore, the exon/intron boundaries of the mouse and human genes are identically positioned. Through targeted disruption of the mouse Aga gene in embryonic stem cells, Kaartinen et al. (1996) generated mice that completely lack Aga activity. At the age of 5 to 10 months, a massive accumulation of aspartylglucosamine was detected in Aga-null mice along with lysosomal vacuolization, axonal swelling in the gracile nucleus, and impaired neuromotor coordination. A significant number of older male mice had massively swollen bladders, which was not caused by obstruction, but was most likely related to the impaired function of the nervous system. The findings were considered consistent with the pathogenesis of AGU and provided further data explaining the impaired neurologic function in AGU patients.

Gonzalez-Gomez et al. (1998) reported that after the age of 10 months the general condition of the null mutant mice created by Kaartinen et al. (1996) gradually deteriorated. They suffered from progressive motor impairment and impaired bladder function and died prematurely. A widespread lysosomal hypertrophy in the central nervous system was detected. The oldest animals (20 months old) displayed neuronal loss and gliosis, particularly in the regions where the most severe neuronal vacuolation was found. The severe ataxic gait of the older mice was probably due to the dramatic loss of Purkinje cells, intensive astrogliosis and vacuolation of neurons in the deep cerebellar nuclei, and the severe vacuolation of the cells in vestibular and cochlear nuclei. The impaired bladder function and subsequent hydronephrosis were secondary to involvement of the central nervous system. The mice thus appeared to be a suitable animal model for testing therapeutic strategies in AGU.

ALLELIC VARIANTS
(selected examples)

.0001 ASPARTYLGLUCOSAMINURIA, FINNISH TYPE [AGA, CYS163SER]

By direct sequencing of PCR-amplified AGA cDNA from an AGU patient, Ikonen et al. (1991) found a G-to-C mutation resulting in the substitution of serine for cysteine-163. 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 cys163-to-ser mutation is responsible for enzyme deficiency, whereas the arg161-to-gln 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 G482A transition and the G488C 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.

.0002 ASPARTYLGLUCOSAMINURIA [AGA, GLY302ARG]

In a 10-year-old Turkish child with AGU, Ikonen et al. (1991) found a G-to-A substitution at nucleotide 904 resulting in substitution of arginine for glycine-302. The patient was homozygous for the mutation and showed fibroblast AGA activity about 7% of normal. The parents were first cousins.

.0003 ASPARTYLGLUCOSAMINURIA [AGA, CYS306ARG]

In a 16-year-old American white patient, Ikonen et al. (1991) found by the SSCP method a T-to-C change at nucleotide 916 resulting in substitution of arginine for cysteine-306.

.0004 ASPARTYLGLUCOSAMINURIA [AGA, GLY60ASP]

In a 3-year-old German child reported by Ziegler et al. (1989), Ikonen et al. (1991) found a G-to-A substitution at nucleotide 179 resulting in substitution of the negatively charged aspartic acid for uncharged glycine at residue 60.

.0005 ASPARTYLGLUCOSAMINURIA [AGA, ALA101VAL]

In a 1-year-old Italian child, Ikonen et al. (1991) found a C-to-T transition at nucleotide 302 that changed alanine-101 to valine. The patient was homozygous for this mutation which was discovered by the SSCP method. The same mutation was found in a compound heterozygote, an English patient (see 208400.0006).

.0006 ASPARTYLGLUCOSAMINURIA [AGA, 7-BP DEL, NT102-108DEL, FS34TER]

In a 5-year-old English child, Ikonen et al. (1991) found compound heterozygosity for the ala101-to-val mutation and a 7-nucleotide deletion (nucleotides 102-108). The gene deletion would be predicted to result in the formation of a truncated polypeptide chain of only 33 amino acids.

.0007 ASPARTYLGLUCOSAMINURIA [AGA, 1-BP INS, FS319TER]

In a 17-year-old Spanish-American patient, Ikonen et al. (1991) found insertion of a single thymidine after nucleotide 800, 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.

.0008 ASPARTYLGLUCOSAMINURIA [AGA, 6-BP INS]

In a 3-year-old Tunisian child, the offspring of first-cousin parents, Ikonen et al. (1991) found homozygosity for a 6-nucleotide insertion (ATGCGG) after nucleotide 127 causing an in-frame insertion of aspartic acid and alanine after amino acid 42.

.0009 ASPARTYLGLUCOSAMINURIA [AGA, IVS8, G-T, +1]

In a 12-year-old black American patient (Hreidarsson et al., 1983; Camden number GM03560), Ikonen et al. (1991) found homozygosity for a deletion of nucleotides 807-940. In this patient 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. Thus 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.

.0010 ASPARTYLGLUCOSAMINURIA [AGA, 1-BP DEL, FS127TER]

In an 8-year-old Dutch child, Ikonen et al. (1991) found deletion of 1 nucleotide, thymidine-800. This resulted in frameshift and premature termination of the polypeptide chain after 126 amino acids.

.0011 MOVED TO 208400.0009

.0012 ASPARTYLGLUCOSAMINURIA [AGA, SER72PRO ]

Peltola et al. (1996) reported that a T-to-C change at codon 214, leading to a ser72-to-pro substitution, occurred in affected members in 4 Arab families with aspartylglucosaminuria. 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.

SEE ALSO

Aula et al. (1984); Aula et al. (1984); Ikonen et al. (1991); Ikonen et al. (1991); Isenberg and Sharp (1976); Mononen et al. (1992); Mononen et al. (1991)

REFERENCES

1. Arvio, M.; Sauna-aho, O.; Peippo, M. :

Bone marrow transplanation for aspartylglucosaminuria: follow-up study of transplanted and non-transplanted patients. J. Pediat. 138: 288-290, 2001.
PubMed ID : 11174635

2. Arvio, P.; Arvio, M.; Kero, M.; Pirinen, S.; Lukinmaa, P.-L. :

Overgrowth of oral mucosa and facial skin, a novel feature of aspartylglucosaminuria. J. Med. Genet. 36: 398-404, 1999.
PubMed ID : 10353787

3. 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.

4. 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 ID : 6517050

5. 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 ID : 6507482

6. Autio, S. :

Aspartylglucosaminuria (AGU).In: Eriksson, A. W.; Forsius, H. R.; Nevanlinna, H. R.; Workman, P. L.; Norio, R. K. : Population Structure and Genetic Disorders. New York: Academic Press (pub.) 1980. Pp. 577-582.

7. Autio, S.; Palo, J.; Perheentupa, J. :

Aspartylglycosaminuria: a gargoyle-like syndrome with autosomal recessive inheritance. Birth Defects Orig. Art. Ser. X(4): 193-200, 1974.

8. Borud, O.; Torp, K. H. :

Aspartylglycosaminuria in northern Norway (Letter) Lancet I: 1082-1083, 1976.

9. Chitayat, D.; Nakagawa, S.; Marion, R. W.; Sachs, G. S.; Hahm, S. Y. E.; Goldman, H. S. :

Aspartylglucosaminuria in a Puerto Rican family: additional features of a panethnic disorder. Am. J. Med. Genet. 31: 527-532, 1988.
PubMed ID : 3228136

10. 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 ID : 1505217

11. 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 ID : 1904874

12. Fisher, K. J.; Tollersrud, O. K.; Aronson, N. N., Jr. :

Molecular genetics of aspartylglucosaminuria. (Abstract) Nucleic Acids Res. Symp. 23: 8 only, 1991.

13. 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.
PubMed ID : 2401370

14. Fountain, R. B. :

Personal Communication. Lincoln, England, 10/14/1977.

15. Fountain, R. B. :

Familial bone abnormalities, deaf mutism, mental retardation and skin granuloma. Proc. Roy. Soc. Med. 67: 878-879, 1974.
PubMed ID : 4431800

16. Gehler, J.; Sewell, A. C.; Becker, C.; Hartmann, J.; Spranger, J. :

Clinical and biochemical delineation of aspartyl-glycosaminuria as observed in two members of an Italian family. Helv. Paediat. Acta 36: 179-189, 1981.
PubMed ID : 6788730

17. Gehler, J.; Sewell, A. C.; Becker, C.; Spranger, J.; Hartmann, J. :

Aspartylglycosaminuria in an Italian family: clinical and biochemical characteristics. J. Inherit. Metab. Dis. 4: 229-230, 1981.
PubMed ID : 6796777

18. Gonzalez-Gomez, I.; Mononen, I.; Heisterkamp, N.; Groffen, J.; Kaartinen, V. :

Progressive neurodegeneration in aspartylglycosaminuria mice. Am. J. Path. 153: 1293-1300, 1998.
PubMed ID : 9777961

19. Gordon, B. A.; Rupar, C. A.; Rip, J. W.; Haust, M. D.; Coulter-Mackie, M. B.; Scott, E.; Hinton, G. G. :

Aspartylglucosaminuria in a Canadian family. Clin. Invest. Med. 21: 114-123, 1998.
PubMed ID : 9627765

20. Gron, K.; Aula, P.; Peltonen, L. :

Linkage analysis of AGA and four marker loci on the long arm of chromosome 4 in families with aspartylglucosaminuria. (Abstract) Cytogenet. Cell Genet. 51: 1008 only, 1989.

21. Gron, K.; Aula, P.; Peltonen, L. :

Linkage of aspartylglucosaminuria (AGU) to marker loci on the long arm of chromosome 4. Hum. Genet. 85: 233-236, 1990.
PubMed ID : 1973404

22. 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 ID : 1877620

23. 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 ID : 6883788

24. 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 ID : 1722323

25. 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 ID : 1703489

26. 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 ID : 1765378

27. Ikonen, E.; Peltonen, L. :

Mutations causing aspartylglucosaminuria (AGU): a lysosomal accumulation disease. Hum. Mutat. 1: 361-365, 1992.
PubMed ID : 1301945

28. Isenberg, J. N.; Sharp, H. L. :

Aspartylglucosaminuria--psychomotor retardation masquerading as a mucopolysaccharidosis. J. Pediat. 86: 713-717, 1975.
PubMed ID : 805826

29. Isenberg, J. N.; Sharp, H. L. :

Aspartylglucosaminuria--unique biochemical and ultrastructural characteristics. Hum. Path. 7: 469-481, 1976.
PubMed ID : 939543

30. 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 ID : 7627186

31. Jenner, F. A.; Pollitt, R. J. :

Large quantities of 2-acetamido-1-(beta-L-aspartamido)-1,2-dideoxyglucose in the urine of mentally retarded siblings. Biochem. J. 103: 48P-49P, 1967.

32. Kaartinen, V.; Mononen, I.; Voncken, J. W.; Noronkoski, T.; Gonzalez-Gomez, I.; Heisterkamp, N.; Groffen, J. :

A mouse model for the human lysosomal disease aspartylglycosaminuria. Nature Med. 2: 1375-1378, 1996.
PubMed ID : 8946839

33. 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 ID : 9137882

34. Maury, C. P. J. :

Accumulation of glycoprotein-derived metabolites in neural and visceral tissues in aspartylglycosaminuria. J. Lab. Clin. Med. 96: 838-844, 1980.
PubMed ID : 7419967

35. 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 ID : 1737774

36. 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 ID : 2011603

37. Mononen, I.; Ylikangas, P.; Mononen, T.; Savolainen, K. :

Neonatal detection of aspartylglycosaminuria. (Letter) Lancet 343: 1297-1298, 1994.
PubMed ID : 7910306

38. Mononen, T.; Mononen, I.; Matilainen, R.; Airaksinen, E. :

High prevalence of aspartylglycosaminuria among school-age children in eastern Finland. Hum. Genet. 87: 266-268, 1991.
PubMed ID : 1864600

39. 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 ID : 1733831

40. Musumeci, S.; Salvati, A.; Schiliro, G.; Salvo, G.; Di Dio, R.; Caprari, P. :

Homozygous NADH-methemoglobin reductase and aspartylglucosaminidase deficiencies in a moderately retarded Sicilian child. Am. J. Med. Genet. 19: 643-650, 1984.
PubMed ID : 6517093

41. Oinonen, C.; Tikkanen, R.; Rouvinen, J.; Peltonen, L. :

Three-dimensional structure of human lysosomal aspartylglucosaminidase. Nature Struct. Biol. 2: 1102-1108, 1995.
PubMed ID : 8846222

42. Palo, J. :

Prevalence of phenylketonuria and some other metabolic disorders among mentally retarded patients in Finland. Acta Neurol. Scand. 43: 573-579, 1967.
PubMed ID : 6083364

43. Palo, J.; Mattsson, K. :

Eleven new cases of aspartylglycosaminuria. J. Ment. Defic. Res. 14: 168-173, 1970.
PubMed ID : 5512217

44. 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 ID : 8776587

45. Pollitt, R. J.; Jenner, F. A.; Merskey, H. :

Aspartylglycosaminuria: an inborn error of metabolism associated with mental defect. Lancet II: 253-255, 1968.

46. 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 ID : 11309371

47. Stevenson, R. E.; Taylor, H. A.; Wilkes, G. :

Aspartylglucosaminuria. Proc. Greenwood Genet. Center 1: 69-72, 1982.

48. 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 ID : 8586423

49. Tollersrud, O. K.; Aronson, N. N., Jr. :

Purification and characterization of rat liver glycosylasparaginase. Biochem. J. 260: 101-108, 1989.
PubMed ID : 2775174

50. 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 ID : 8064811

51. Vargas-Diez, E.; Chabas, A.; Coll, M. J.; Sanchez-Perez, J.; Garcia-Diez, A.; Fernandez-Herrera, J. M. :

Angiokeratoma corporis diffusum in a Spanish patient with aspartylglucosaminuria. Brit. J. Derm. 147: 760-764, 2002.
PubMed ID : 12366426

52. Yoshida, K.; Ikeda, S.; Yanagisawa, N.; Yamauchi, T.; Tsuji, S.; Hirabayashi, Y. :

Two Japanese cases with aspartylglycosaminuria: clinical and morphological features. Clin. Genet. 40: 318-325, 1991.
PubMed ID : 1756604

53. Yoshida, K.; Ikeda, S.; Yanagisawa, N.; Yamauchi, T.; Tsuji, S.; Hirabayashi, Y. :

Two Japanese cases with aspartylglycosaminuria: clinical and morphological features. Clin. Genet. 40: 318-325, 1991.
PubMed ID : 1756604

54. 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.

55. Zlotogora, J.; Ben-Neriah, Z.; Abu-Libdeh, B. Y.; Sury, V.; Zeigler, M. :

Aspartylglucosaminuria among Palestinian Arabs. J. Inherit. Metab. Dis. 20: 799-802, 1997.
PubMed ID : 9427148

CONTRIBUTORS

Gary A. Bellus - updated : 4/11/2003
George E. Tiller - tiller : 10/2/2001
Ada Hamosh - updated : 4/23/2001
Michael J. Wright - updated : 7/12/1999
Victor A. McKusick - updated : 3/11/1999
Victor A. McKusick - updated : 1/20/1999
Victor A. McKusick - updated : 2/19/1998
Victor A. McKusick - updated : 1/6/1998
Victor A. McKusick - updated : 6/27/1997
Moyra Smith - updated : 6/22/1996

CREATION DATE

Victor A. McKusick : 6/3/1986

EDIT HISTORY

carol : 6/7/2005
carol : 6/17/2004
alopez : 3/17/2004
alopez : 4/11/2003
cwells : 10/10/2001
cwells : 10/2/2001
cwells : 5/9/2001
cwells : 5/8/2001
terry : 4/23/2001
jlewis : 7/23/1999
jlewis : 7/19/1999
terry : 7/12/1999
carol : 3/16/1999
terry : 3/11/1999
carol : 1/29/1999
terry : 1/20/1999
carol : 9/28/1998
carol : 6/26/1998
terry : 6/4/1998
mark : 2/25/1998
terry : 2/19/1998
terry : 1/6/1998
alopez : 7/3/1997
jenny : 7/2/1997
mark : 7/1/1997
terry : 6/27/1997
alopez : 6/10/1997
carol : 6/24/1996
carol : 6/23/1996
carol : 6/22/1996
mark : 1/14/1996
mark : 12/6/1995
terry : 8/30/1994
davew : 8/17/1994
jason : 6/16/1994
mimadm : 4/18/1994
warfield : 4/14/1994
pfoster : 4/1/1994

Copyright © 1966-2007 Johns Hopkins University