Aspartylglucosaminuria: cDNA encoding human aspartylglucosaminidase and the missense mutation causing the disease.

Ikonen, Elina; Baumann, Marc; Grön, K; Syvänen, Ann‐Christine; Enomaa, N; Halila, Ritva; Aula, P; Peltonen, Leena

doi:10.1002/j.1460-2075.1991.tb07920.x

Cited by 121 publications

(95 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We found His204, which is located in hydrophilic stretch of 11 amino acids in the AG (Ikonen et al, 1991a) (Neufeld, 1981 Analogous removal of short peptides has been described for sosomes, the the a and 3 chains of lysosomal hexosaminidase. In these mmed to the polypeptides, however, the removed amino acids remain attached to the mature enzyme complex by disulfide bridges (Hubbes et al, 1989;Quon et al, 1989).…”

Section: Discussionsupporting

confidence: 61%

Lysosomal aspartylglucosaminidase is processed to the active subunit complex in the endoplasmic reticulum.

et al. 1993

Self Cite

View full text Add to dashboard Cite

Aspartylglucosaminidase (AGA) is a lysosomal enzyme, the deficiency of which leads to a human storage disease, aspartylglucosaminuria (AGU). Although numerous mutations have been identified in AGU patients, elucidation of the molecular pathogenesis of the disease has been hampered by the missing information on the cellular events resulting in the maturation and activation of the enzyme. Here we used the expression of in vitro mutagenized constructs of the AGA cDNA to define three specific proteolytic trimming steps resulting in mature AGA. Removal of the signal peptide is immediately followed by proteolytic cleavage of the precursor into two subunits and results in biologically active enzyme already in the endoplasmic reticulum. This early activation has not previously been described for lysosomal enzymes. The subsequent lysosomal trimming does not influence the enzymatic activity of AGA. It consists only of a single proteolytic cleavage which removes 10 amino acids from the C‐terminal end of the larger subunit, in contrast to the multistep lysosomal processing observed in several other hydrolases.

show abstract

Section: Discussionsupporting

confidence: 61%

Lysosomal aspartylglucosaminidase is processed to the active subunit complex in the endoplasmic reticulum.

et al. 1993

Self Cite

View full text Add to dashboard Cite

show abstract

“…The vertical columns (A-D) contain pairs of allele-specific primers for each site ordered into nine horizontal rows (1-9). The acronyms corresponding to the diseases and the mutant or variant nucleotides analyzed on the array are given in the lower part of A. INCL = infantile neuronal ceroid lipofuscinosis (Vesa et al 1995); AGU = aspartylglucosaminuria (Ikonen et al 1991); FV = Factor V Leiden (Bertina et al 1994); CCD = congenital chloride diarrhea (Höglund et al 1996); APECED = autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (the Finnish-German APECED Consortium 1997); HTI = hereditary tyrosinemia type I (St-Louis et al 1994); HFI = hereditary fructose intolerance (Cross et al 1990); OAT1 & 2 = gyrate atrophy of the choroid and retina (Mitchell et al1989); Batten = Batten disease (the International Batten Disease Consortium 1995); vLINCL = variant late infantile neuronal ceroid lipofuscinosis (Savukoski et al 1998); NKH = nonketotic hyperglycinemia (Kure et al 1992); CF ⌬508/⌬TT394 = cystic fibrosis (Kere et al 1994); A1AT = ␣1-antitrypsin deficiency Z-mutation (Cox et al 1988); HH = hereditary hemochromatosis C282Y (Feder et al 1996); DFNB=nonsyndromic deafness, connexin 26 35insG (Denoyelle et al 1997); ODG = hypergonadotropic ovarian dysgenesis (Aittomaki et al 1995); DTD = diastrophic dysplasia (Hästbacka et al submitted); CNFmaj/min = congenital nephrosis (Kestilä et al 1998); PKU R408W = phenylketonuria (Guldberg et al 1995); MCAD = medium-chain acyl-CoA dehydrogenase deficiency (Matsubara et al 1990); LCHAD = long-chain 3-hydroxyacylCoA dehydrogenase deficiency (Ijist et al 1996); PT = prothrombin G20210A (Poort et al 1996); MPS = mucopolysaccharidosis type I (Bunge et al 1994); RS1/2 = X-linked juvenile retinoschisis (Huopaniemi et al 1999); LPI = lysinuric protein intolerance (Torrents et al 1999); Salla = Salla disease (Verheijen et al 1999); SNP1 = WIAF-11062, SNP2 = WIAF-11091, SNP6 = WIAF-10964 (Cargill et al 1999); SNP7 = HLA-H IVS2 (Beutler et al 1996); SNP8 = HLA-H 5569 (Jeffrey et al 1999) ; EPMR = progressive epilepsy with mental retardation …”

Section: Array Design and Genotyping Capacitymentioning

confidence: 99%

A System for Specific, High-throughput Genotyping by Allele-specific Primer Extension on Microarrays

Pastinen¹,

Raitio²,

Lindroos³

et al. 2000

Genome Res.

314

218

View full text Add to dashboard Cite

This study describes a practical system that allows high-throughput genotyping of single nucleotide polymorphisms (SNPs) and detection of mutations by allele-specific extension on primer arrays. The method relies on the sequence-specific extension of two immobilized allele-specific primers that differ at their 3Ј-nucleotide defining the alleles, by a reverse transcriptase (RT) enzyme at optimized reaction conditions. We show the potential of this simple one-step procedure performed on spotted primer arrays of low redundancy by generating over 8000 genotypes for 40 mutations or SNPs. The genotypes formed three easily identifiable clusters and all known genotypes were assigned correctly. Higher degrees of multiplexing will be possible with this system as the power of discrimination between genotypes remained unaltered in the presence of over 100 amplicons in a single reaction. The enzyme-assisted reaction provides highly specific allele distinction, evidenced by its ability to detect minority sequence variants present in 5% of a sample at multiple sites. The assay format based on miniaturized reaction chambers at standard 384-well spacing on microscope slides carrying arrays with two primers per SNP for 80 samples results in low consumption of reagents and makes parallel analysis of a large number of samples convenient. In the assay one or two fluorescent nucleotide analogs are used as labels, and thus the genotyping results can be interpreted with presently available array scanners and software. The general accessibility, simple set-up, and the robust procedure of the array-based genotyping system described here will offer an easy way to increase the throughput of SNP typing in any molecular biology laboratory.

show abstract

“…The mutations were selected as targets because they occur with a high frequency in the Finnish population and populationbased screening for them would be clinically relevant. Five of the mutations cause severe recessive disorders [infantile neuronal ceroid lipofuscinosis (INCL; Vesa et al 1995), aspartylglucosaminuria (AGU; Ikonen et al 1991), gyrate atrophy (GA; Mitchell et al 1989) and nonketotic hyperglycinemia (NKH; Kure et al 1992)] belonging to the ''Finnish disease heritage,'' (for review, see Peltonen et al 1995) and occur with a combined population frequency of carriers of ∼0.05. Three mutations in the low-density lipoprotein receptor (LDLR) gene (Aalto-Setälä et al 1989;Koivisto et al 1991Koivisto et al , 1995 that cause familial hypercholesterolemia (FH) with the estimated prevalence of 1 in 500, both in Finland and worldwide, were also included in the panel.…”

mentioning

confidence: 99%

Minisequencing: A Specific Tool for DNA Analysis and Diagnostics on Oligonucleotide Arrays

Pastinen¹,

Kurg²,

Metspalu³

et al. 1997

Genome Res.

296

171

View full text Add to dashboard Cite

We describe a method for multiplex detection of mutations in which the solid-phase minisequencing principle is applied to an oligonucleotide array format. The mutations are detected by extending immobilized primers that anneal to their template sequences immediately adjacent to the mutant nucleotide positions with single labeled dideoxynucleoside triphosphates using a DNA polymerase. The arrays were prepared by coupling one primer per mutation to be detected on a small glass area. Genomic fragments spanning nine disease mutations, which were selected as targets for the assay, were amplified in multiplex PCR reactions and used as templates for the minisequencing reactions on the primer array. The genotypes of homozygous and heterozygous genomic DNA samples were unequivocally defined at each analyzed nucleotide position by the highly specific primer extension reaction. In a comparison to hybridization with immobilized allele-specific probes in the same assay format, the power of discrimination between homozygous and heterozygous genotypes was one order of magnitude higher using the minisequencing method. Therefore, single-nucleotide primer extension is a promising principle for future high-throughput mutation detection and genotyping using high density DNA-chip technology.The Human Genome Project will generate a nucleotide sequence of the genome within a few years. Detailed information of all human genes will speed up the identification of mutations that either cause inherited disorders or predispose to multifactorial diseases. Consequently, more efficient methods with the capacity to analyze interindividual sequence variation on a large scale will be required. A promising approach toward cost-efficient DNA diagnostics and comparative sequence analysis is to use arrays of oligonucleotides (DNA chips) as solid support in miniaturized assays (for review, see Southern 1996). The concept of oligonucleotide arrays was originally introduced for de novo nucleotide sequencing by hybridization (Khrapko et al. 1991). Sophisticated technology has been developed for the production of high-density oligonucleotide arrays (Fodor et al. 1991;Pease et al. 1994;McGall et al. 1996), and systems for fluorescence detection and data analysis for this assay format are also under development (Schena et al. 1995).Despite the impressive technology that is emerging for hybridization to oligonucleotide arrays, a problem originating from the inherent properties of the nucleic acid hybridization reaction itself is a limiting factor in these methods, particularly when single-nucleotide variations are analyzed. The efficiency of hybridization and the thermal stability of hybrids formed between the target nucleic acid and a short oligonucleotide probe depend strongly on the nucleotide sequence of the probe and the stringency of the reaction conditions (Conner et al. 1983). Moreover, the degree of destabilization of the hybrid molecule by a mismatched nucleotide at one position is dependent on the flanking nucleotide sequence. Consequently, it is ...

show abstract

Aspartylglucosaminuria: cDNA encoding human aspartylglucosaminidase and the missense mutation causing the disease.

Cited by 121 publications

References 31 publications

Lysosomal aspartylglucosaminidase is processed to the active subunit complex in the endoplasmic reticulum.

Lysosomal aspartylglucosaminidase is processed to the active subunit complex in the endoplasmic reticulum.

A System for Specific, High-throughput Genotyping by Allele-specific Primer Extension on Microarrays

Minisequencing: A Specific Tool for DNA Analysis and Diagnostics on Oligonucleotide Arrays

Contact Info

Product

Resources

About