Candidate genes.

refine your query
genesymbol type description chr. startpos endpos synonyms
NEIL3 protein-coding nei like DNA glycosylase 3 4 178230991 178284092 hFPG2, FLJ10858, FPG2, hNEI3, FGP2, NEI3, ZGRF3
  links NCBI   ENSEMBL  SwissProt  GeneCards   STRING   PubMed  create primers for all transcripts
  KEGG pathways Base excision repair
  PFAM GRF zinc finger, Formamidopyrimidine-DNA glycosylase H2TH domain, Zn-finger in Ran binding protein and others
  InterPro domains Zinc finger, DNA glycosylase/AP lyase-type, Zinc finger, RanBP2-type, Zinc finger, GRF-type, Ribosomal protein S13-like, H2TH, DNA glycosylase/AP lyase, catalytic domain, DNA glycosylase/AP lyase, H2TH DNA-binding, DNA glycosylase/AP lyase, zinc finger domain, DNA-binding site
  paralogs NEIL2 (10%)
DESCRIPTION NEIL3 belongs to a class of DNA glycosylases homologous to the bacterial Fpg/Nei family. These glycosylases initiate the first step in base excision repair by cleaving bases damaged by reactive oxygen species and introducing a DNA strand break via the associated lyase reaction (Bandaru et al., 2002). CLONING By searching a database for sequences similar to the Arabidopsis DNA glycosylase Fpg, Bandaru et al. (2002) identified NEIL3. Bacterial Fpg/Nei proteins contain 2 structural domains: an N-terminal 2-layered beta sandwich and a C-terminal 4-helix bundle, which includes a helix-2-turns-helix (H2TH) motif and a zinc finger. The deduced 605-amino acid human NEIL3 protein has conserved residues in 6 highly conserved regions that span both structural domains of the bacterial Fpg/Nei proteins. In addition, NEIL3 has a C-terminal extension similar to portions of topoisomerases (see TOP2A; 126430) and apurinic/apyrimidinic endonucleases (see APEX; 107748), as well as a different zinc finger motif. By searching for sequences similar to E. coli Fpg and Nei, followed by RT-PCR of HeLa cell mRNA, Morland et al. (2002) cloned NEIL3, which they designated FPG2. The deduced 605-amino acid protein has a calculated molecular mass of 67.9 kD. Unlike NEIL1 (608844), NEIL3 contains a RAN-binding protein (see 601180)-like zinc finger motif and C-terminal zinc ribbon domains. Northern blot analysis of several human tissues detected a 2.4-kb transcript only in testis and thymus. Fluorescence-tagged NEIL3 colocalized with RPA2 (179836) in the nuclei of transfected HeLa cells and was excluded from nucleoli. GENE STRUCTURE Bandaru et al. (2002) and Morland et al. (2002) determined that the NEIL3 gene contains 10 exons. Morland et al. (2002) determined that the gene spans about 55 kb. Exon 1 is embedded within a CpG island. MAPPING By genomic sequence analysis, Bandaru et al. (2002) and Morland et al. (2002) mapped the NEIL3 gene to chromosome 4q34.2.
See report at OMIM's website.

  • hFPG1 and hFPG2 repair 8-oxoguanine and other DNA oxidation products. (hFPG1 and hFPG2)
  • Observational study and meta-analysis of gene-disease association. (HuGE Navigator)
  • Observational study of gene-disease association and gene-gene interaction. (HuGE Navigator)
  • NEIL3 partially rescues an E. coli nth nei mutant from hydrogen peroxide sensitivity. Taken together, repair of certain base damage including base loss in ssDNA may be mediated by NEIL3.
  • both the transcription and protein levels of hNEIL3 fluctuated during the cell cycle
  • Here we report the construction of bicistronic expression vectors for expressing in Escherichia coli the full-length mouse Neil3 (MmuNeil3), its glycosylase domain (MmuNeil3Delta324), as well as the glycosylase domain of human Neil3 (NEIL3Delta324).
  • Results show that the base excision and strand incision activities of NEIL3 exhibited a non-concerted action, indicating that NEIL3 mainly operates as a monofunctional DNA glycosylase.
  • one role for Neil3 and NEIL1 is to repair DNA base damages in telomeres in vivo and that Neil3 and Neil1 may function in quadruplex-mediated cellular events, such as gene regulation via removal of damaged bases from quadruplex DNA.
  • Polymorphisms within FLT3, EGFR, NEIL3, and ALOX5 may contribute to the occurrence of GBM.
  • NEIL3 rs12645561 SNP TT genotype was associated with increased risk of myocardial infarction.
  • The abnormal expressions of NEIL1, NEIL2, and NEIL3 are involved in cancer through their association with the somatic mutation load.
  • SNPs in NEIL3 are associated with impulsivity in Native American sample.
  • Results suggest a novel role for the DNA glycosylase Neil3 in atherogenesis in balancing lipid metabolism and macrophage function, potentially independently of genome-wide canonical base excision repair of oxidative DNA damage.
  • These findings demonstrate that deficiency in NEIL3 is associated with increased lymphocyte apoptosis, autoantibodies, and predisposition to autoimmunity.
  • Single nucleotide polymorphism (SNP) rs142310826 near the NEIL3 gene showed a genome-wide significant interaction with caffeine consumption .There was no gender difference for this interaction (P = 0.64 for heterogeneity). NEIL3, a gene belonging to [...]
  • NEIL3-dependent modulation of DNA methylation regulates cardiac fibroblast proliferation and thereby affects extracellular matrix modulation after myocardial infarction.
  • Data indicate that DNA glycosylases MYH, UNG2, MPG, NTH1, NEIL1, 2 and 3 on nascent DNA.
  • NEIL3 protects genome stability through targeted repair of oxidative damage in telomeres during S/G2 phase.
  • NEIL3 cleaves psoralen-induced DNA-DNA cross-links in three-stranded and four-stranded DNA substrates to generate unhooked DNA fragments containing either an abasic site or a psoralen-thymine monoadduct. Nei and NEIL1 also cleave a psoralen-induced f [...]
  • This study identifies the NEIL3 promoter possessing a G-rich element that can adopt a G4 fold, and when 8-oxo-7,8-dihydroguanine is incorporated, the sequence can lock into a more stable G4 fold via recruitment of the fifth track of Gs.
  • NEIL1 and NEIL3 may protect cells against cytotoxic and mutagenic effects of NM-Fapy-dG, but NEIL1 may have a unique role in initiation of base excision repair of AFB1-Fapy-dG
  • Results indicate that whilst specificity for 5-hydroxyuracil and thymine glycol was observed, NEIL3 preferentially excises oxidized bases from single stranded DNA and within open fork structures.
  • TRAIP is important for the recruitment of NEIL3 but not FANCD2, and knockdown of TRAIP promotes FA/BRCA pathway activation. Interestingly, TRAIP is non-epistatic with both NEIL3 and FA pathways in psoralen-ICL repair, suggesting that TRAIP may functi [...]
  • An autoinhibitory role for the GRF zinc finger domain of DNA glycosylase NEIL3.
  • DNA glycosylase Neil3 regulates vascular smooth muscle cell biology during atherosclerosis development.
  • Deficiency of NEIL3 Enhances the Chemotherapy Resistance of Prostate Cancer.
  •   MGD
  • homeostasis/metabolism phenotype
  • immune system phenotype
  • cellular phenotype
  • nervous system phenotype
  • hematopoietic system phenotype
  • normal phenotype
  •   transcripts ENST00000264596: 2408 bases (protein_coding)
    ENST00000513321: 1528 bases (nonsense_mediated_decay)
      interactions (STRING)
    APEX1: (textmining 668)    BMP2K: (textmining 467)    CD97: (textmining 556)    DCLRE1C: (textmining 495)   
    ERCC5: (textmining 483)    GTF2H1: (textmining 657)    LIG3: (textmining 537)    NEIL1: (textmining 903)   
    NTHL1: (textmining 740)    NUDT1: (textmining 543)    OGG1: (textmining 736)    RPA2: (textmining 645)   
    TOP2A: (textmining 560)    TWSG1: (textmining 449)    XRCC1: (textmining 422)   
  • bubble DNA binding
  • damaged DNA binding
  • double-stranded DNA binding
  • single-stranded DNA binding
  • DNA-(apurinic or apyrimidinic site) lyase activity
  • nucleus
  • base-excision repair
  • nucleotide-excision repair
  • zinc ion binding
  • DNA N-glycosylase activity
  • AGA protein-coding aspartylglucosaminidase 4 178351928 178363657 AGU, ASRG, GA
      links NCBI   ENSEMBL  SwissProt  GeneCards   STRING   PubMed  create primers for all transcripts
      KEGG pathways Other glycan degradation, Lysosome
      PFAM Asparaginase
      InterPro domains Peptidase T2, asparaginase 2, Nucleophile aminohydrolases, N-terminal
      paralogs TASP1 (21%), ASRGL1 (28%)
  • Short stature
  • Platyspondyly
  • Macroglossia
  • Aspartylglucosaminuria
  • Carious teeth
  • Delayed speech and language development
  • Spondylolisthesis
  • Hoarse voice
  • Coarse facial features
  • Neurological speech impairment
  • Brachycephaly
  • Mitral regurgitation
  • Spasticity
  • Diarrhea
  • Kyphosis
  • Joint laxity
  • Thick lower lip vermilion
  • Autosomal recessive inheritance
  • Thickened calvaria
  • Abnormality of metabolism/homeostasis
  • Beaking of vertebral bodies
  • Abnormality of movement
  • Hypertelorism
  • Otitis media
  • Arthritis
  • Acne
  • Pes planus
  • Spondylolysis
  • Pectus carinatum
  • Wide mouth
  • Cerebral atrophy
  • Malabsorption
  • Hepatomegaly
  • Sleep disturbance
  • Mandibular prognathia
  • Delayed skeletal maturation
  • Pathologic fracture
  • Intellectual disability
  • Abnormal cortical bone morphology
  • Depressed nasal bridge
  • Abnormality of the tongue
  • Macroorchidism
  • Short nose
  • Hernia
  • Seizures
  • Angiokeratoma corporis diffusum
  • Vacuolated lymphocytes
  • Cognitive impairment
  • Limitation of joint mobility
  • Scoliosis
  • Cataract
  • Muscular hypotonia
  • Umbilical hernia
  • Craniofacial hyperostosis
  • Splenomegaly
  • Abnormality of the outer ear
  • Recurrent respiratory infections
  • Anteverted nares
  • Broad face
  • Abnormality of the ulna
  • Hypoplastic frontal sinuses
  • Large face
  • Neutropenia
  • Developmental regression
  • Microcephaly
  • Dysostosis multiplex
  • Gingival overgrowth
    INHERITANCE: Autosomal recessive GROWTH: [Height]; Short stature HEAD AND NECK: [Head]; Brachycephaly; Microcephaly; [Face]; Coarse facies; Broad face; [Eyes]; Crystal-like lens opacity; [Nose]; Low nasal bridge; Anteverted nostrils; [Mouth]; Macroglossia; Wide mouth; Thick lips CARDIOVASCULAR: [Heart]; Mitral insufficiency RESPIRATORY: [Lung]; Recurrent respiratory infections ABDOMEN: [External features]; Hernias; [Liver]; Hepatomegaly; [Gastrointestinal]; Diarrhea GENITOURINARY: [External genitalia, male]; Macroorchidism SKELETAL: Delayed skeletal maturation; Mild dysostosis multiplex; [Skull]; Thick calvaria; Underdeveloped frontal sinuses; [Spine]; Kyphosis; Scoliosis; Flattening and anterior beaking of vertebral bodies; Spondylolysis; Spondylolisthesis; [Limbs]; Joint laxity; Pathologic fractures SKIN, NAILS, HAIR: [Skin]; Angiokeratoma corporis diffusum; Acne NEUROLOGIC: [Central nervous system]; Speech delay; Mental deterioration in childhood; Mental retardation; Hypotonia; Spasticity; Cerebral atrophy; Seizures (adult) VOICE: Hoarse voice HEMATOLOGY: Vacuolated lymphocytes; Neutropenia IMMUNOLOGY: Recurrent infections LABORATORY ABNORMALITIES: Aspartylglucosaminuria; Little to absent aspartylglucosaminuria activity; Decreased prothrombin time MISCELLANEOUS: Increased frequency in the Finnish population; 98% of Finnish cases due to one mutation; Carrier frequency in Finland 1/40; Onset of symptoms 2-6 years of age MOLECULAR BASIS: Due to mutation in the aspartylglucosaminidase gene (AGA, 208400.0001)
    A number sign (#) is used with this entry because aspartylglucosaminuria (AGU) is caused by mutation in the AGA gene (613228). DESCRIPTION Aspartylglucosaminuria is a severe autosomal recessive lysosomal storage disorder that involves the central nervous system and causes skeletal abnormalities as well as connective tissue lesions. The most characteristic feature is progressive mental retardation. The disorder is caused by deficient activity of the lysosomal enzyme glycosylasparaginase, which results in body fluid and tissue accumulation of a series of glycoasparagines, i.e., glycoconjugates with an aspartylglucosamine moiety at the reducing end. AGU belongs to the group of disorders commonly referred to as the Finnish disease heritage (summary by Mononen et al., 1993 and Arvio and Arvio, 2002). CLINICAL FEATURES Aspartylglucosaminuria 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 in Finland. The parents of 1 patient were first cousins. 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. Aspartylglucosaminuria has also been observed in Finns living in Norway (Borud and Torp, 1976). 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. Zlotogora et al. (1997) diagnosed this disorder in 8 patients originating from 3 unrelated families, all Palestinian Arabs from the region of Jerusalem. 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. 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. DIAGNOSIS Mononen et al. (1994) described a fluorometric glycosylasparaginase assay for neonatal screening for AGU. Zlotogora et al. (1997) stated that the clinical diagnosis of AGU is difficult, in particular early in the course of the disease; most of the patients are diagnosed after the age of 5 years. They noted that since patients with AGU excrete large amounts of aspartylglucosamine in urine, biochemical detection is easy by urine chromatography. CLINICAL MANAGEMENT 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. MAPPING 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. POPULATION GENETICS Aspartylglucosaminuria occurs worldwide, but is enriched in the Finnish population (Arvio and Arvio, 2002). Palo and Mattsson (1970) estimated that there are at least 130 cases in the total population of 4.5 million in Finland. 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. MOLECULAR GENETICS In Finnish patients with aspartylglucosaminuria, Ikonen et al. (1991) and Fisher and Aronson (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 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 (613228.0001) 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 Finnish C163S founder mutation. 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 causing AGU published to that time. ANIMAL MODEL 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.
    See report at OMIM's website.

    DESCRIPTION Aspartylglucosaminidase (AGA; EC 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). CLONING 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. BIOCHEMICAL FEATURES 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. MAPPING 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. MOLECULAR GENETICS 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.
    See report at OMIM's website.

      OrphaNet Aspartylglucosaminuria   germline (assessed)
  • Molecular mechanism for the autoproteolytic activation of aspartylglucosaminidase.
  • A new point mutation, c.44T>G, found in a Finnish compound heterozygote causes a L15R AA substitution in the signal sequence of the AGA enzyme, affecting AGA translocation by altering a critical hydrophobic core structure in the signal sequence.
  • aspartylglucosaminidase may have a role in development of congenital disorders of glycosylation type I
  • The amino acid substitutions in aspartylglucosaminidase responsible for aspartylglucosaminuria were classified and divided in three groups.
  • Increased AGA plasma activity, although a consistent finding in congenital disorders of glycosylation patients, is not specific to this group of disorders.
  • [review] Natural killer (NK) cell tumors, subtypes of myeloid leukemias and T-cell lymphomas respond to ASNase; ovarian carcinomas and other solid tumors have been proposed as additional targets for ASNase, with a potential role for glutaminase. activity.
  • study reports 2 novel aspartylglucosaminidase gene mutations, one in Qatari twins with an early, perinatal presentation not previously described for aspartylglucosaminuria and the other in 3 Turkish children with newly diagnosed aspartylglucosaminuri [...]
  • We show that gene-silenced cells show specifically reduced AGA activity and store globotriaosylceramide. In gene-silenced cells, release of the neurotransmitter acetylcholine is significantly reduced, demonstrating that this model may be used to stud [...]
  • 1.8A resolution crystal structure of mature G172D mutant of a model missense GA corresponding to a Canadian aspartylglucosaminuria allele; studied the effect of its single amino acid change on substrate processing
  • Determination a 1.6 A-resolution structure of the Finnish AGU model and building of an enzyme-substrate complex to provide a structural basis for analyzing the negative effects of the point mutation on KM and kcat of the mature enzyme.
  • T99K variant of glycosylasparaginase shows a new structural mechanism of the genetic disease aspartylglucosaminuria
  •   MGD
  • nervous system phenotype
  • renal/urinary system phenotype
  • liver/biliary system phenotype
  • behavior/neurological phenotype
  • growth/size/body phenotype
  • mortality/aging
  • integument phenotype
  • homeostasis/metabolism phenotype
  • cellular phenotype
  •   transcripts ENST00000264595: 2107 bases (protein_coding)
    ENST00000510955: 880 bases (retained_intron)
    ENST00000506853: 762 bases (processed_transcript)
    ENST00000511231: 546 bases (retained_intron)
    ENST00000502310: 464 bases (protein_coding)
    ENST00000510635: 414 bases (protein_coding)
      interactions (STRING)
    AGAP1: (textmining 443)    BCS1L: (textmining 426)    BLOC1S3: (textmining 502)    CD2AP: (textmining 625)   
    CLN5: (textmining 451)    CTBS: (textmining 422)    CUTC: (neighborhood 654)    GALNT7: (textmining 502)   
    GLA: (textmining 470)    HGD: (textmining 742)    IGF2R: (experimental 635)    KPNA3: (textmining 413)   
    MANBA: (textmining,neighborhood 444)    PPT1: (textmining 420)    RAB22A: (textmining 443)    SCRG1: (textmining 457)   
    SV2A: (textmining 496)    TFPI: (textmining 645)   
  • N4-(beta-N-acetylglucosaminyl)-L-asparaginase activity
  • lysosome
  • endoplasmic reticulum
  • proteolysis
  • protein deglycosylation
  • peptidase activity
  • protein self-association
  • protein maturation
  • 2 gene(s) (31.264 ms).


    your settings in the query mask this output

    create a BED file

    I want to sequence only the candidate genes shown here, only exons
    complete genes
    flanked by bases on each side.

    citing GeneDistiller

    If you feel that GeneDistiller has helped you in your research, please cite the following publication:

    Seelow D, Schwarz JM, Schuelke M.
    GeneDistiller--distilling candidate genes from linkage intervals.
    PLoS ONE. 2008;3(12):e3874. Epub 2008 Dec 5.

    entitylast update (YYYY-MM-DD)
    Disease Ontology2020-06-29
    Ensembl 84 (GRCh73)2016-06-14
    Entrez gene history2021-10-28
    Entrez gene positions2021-10-28
    Entrez gene RIFS2021-10-28
    Entrez genes2021-10-28
    Entrez gene synonyms2021-10-28
    Human Phenotype Ontology2015-12-22