Spectrum of mutations in aspartylglucosaminuria.

Ikonen, Elina; Aula, Pertti; Grön, K; Tollersrud, O; Halila, Ritva; Manninen, Tuula; Syvänen, Ann‐Christine; Peltonen, Leena

doi:10.1073/pnas.88.24.11222

Cited by 50 publications

(27 citation statements)

References 34 publications

(34 reference statements)

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“…In contrast to a previous study (26) in which 9 out of 10 mutations were found by SSCP analysis, the SSCP technique was relatively inefficient here. Possibly this is partially because only two-thirds of the fibrillin cDNA has been cloned, and consequently all the mutations in the 5' third are undetectable.…”

Section: Resultscontrasting

confidence: 73%

Two mutations in Marfan syndrome resulting in truncated fibrillin polypeptides.

Kainulainen

Sakai

Child

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

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Biochemical and molecular genetic studies have recently suggested that mutations in the gene coding for fibrillin on chromosome 15 result in Marfan syndrome. To our knowledge, only one mutation in the fibrillin gene has been published. Here we report the results of screening 20 unrelated MES patients for mutations in fibrillin cDNA by the singlestrand conformation polymorphism technique. We found two mutations, both of which appear in the heterozygote form and code for a shortened fibrillin polypeptide. The first mutation is a large in-frame deletion of 366 bases of the fibrillin mRNA, shown to result in a truncated but secreted polypeptide found in the fibroblast culture of the patient. The second mutation is a G-to-A transition resulting in the substitution of a stop codon for a tryptophan codon and thus predicting the premature termination of the polypeptide chain. We screened 60 other, unrelated MFS patients for these mutations as well as for the previously reported mutation (arginine-239 to proline) and found none of the three mutations in any of these patients. These data suggest that most MFS families carry their own distinct mutation.The Marfan syndrome (MFS) is an autosomal dominant connective-tissue disorder characterized by cardiovascular, ocular, and skeletal manifestations (1). By the random linkage approach, the MFS locus was assigned to the long arm of chromosome 15 in three Finnish families (2). Later, the linkage was confirmed in families from diverse ethnic backgrounds, and the locus was more precisely localized to the immediate vicinity of the polymorphic marker DISSI (3-5). To date, linkage analyses of chromosome 15 markers in families from different populations have not revealed any evidence for genetic heterogeneity underlying MFS (3-5).Independent simultaneous immunohistochemical analyses demonstrated a nearly constant deficiency of fibrillin, an extracellular protein (6), in skin sections and cultured fibroblasts from MFS patients (7). Subsequently, the fibrillin cDNA was cloned (8) and the corresponding locus was mapped by in situ hybridization to chromosome 15q21.1 (9, 10), in the vicinity of the marker DJSSI. The MATERIALS AND METHODSPatients. The material consisted of fibroblast lines established from skin biopsies of 20 unrelated MFS patients from Finland and the United Kingdom and blood samples of these and 41 additional MFS patients from Belgium, Finland, the Netherlands, Switzerland, the United Kingdom, and the United States, including patients both with and without family history of MFS. All the samples were taken in accordance with the Helsinki Declaration. The diagnoses were made by using the criteria established by Beighton et al. (12).The patient R.H. was a 48-year-old man with cardiovascular, eye, and skeletal symptoms and signs of MFS. He was a member of a three-generation English pedigree none of whom have ectopia lentis. The propositus' mother had peripheral retinal degeneration and retinal detachment. A brother and sister of the propositus had severe mitral va...

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Section: Resultscontrasting

confidence: 73%

Two mutations in Marfan syndrome resulting in truncated fibrillin polypeptides.

Kainulainen

Sakai

Child

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

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“…Due to a founder effect, AGU is enriched in Finland. However, the majority of AGU alleles are found outside Finland with sporadic AGU causing mutations (Aronson, 1999; Hreidarsson et al, 1983; Ikonen et al, 1991; Opladen et al, 2014). …”

Section: Introductionmentioning

confidence: 99%

Structural Basis of a Point Mutation that Causes the Genetic Disease Aspartylglucosaminuria

et al. 2014

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Summary Aspartylglucosaminuria (AGU) is a lysosomal storage disease caused by a metabolic disorder of lysosomes to digest Asn-linked glycoproteins. The specific enzyme linked to AGU is a lysosomal hydrolase called glycosylasparaginase. Crystallographic studies revealed that a surface loop blocks the catalytic center of the mature hydrolase. Autoproteolysis is thus required to remove this P-loop and open up the hydrolase center. Nonetheless, AGU mutations result in misprocessing of their precursors and are deficient in hydrolyzing glycoasparagines. To understand the catalytic and structural consequences of AGU mutations, we have characterized two AGU models, one corresponding to a Finnish allele and the other found in a Canadian family. We also report a 2.1 Å-resolution structure of the latter AGU model. The current crystallographic study provides the first structure of an AGU mutant. It reveals substantial conformation changes at the defective autocleavage site of the AGU mutant, which is trapped as an inactive precursor.

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“…Prior to this case, 15 mutations have been found among the AGU patients from various ethnic backgrounds (Ikonen et al 1991a;Mononen et al 1993;Peltola et al 1994;Jalanko et al 1995). Five of these mutations --two missense mutations from a Finnish AGU patient (Ikonen et al 1991b;Fisher and Aronson 1991a;Mononen et al 1991a) and a British patient ; a nonsense mutation (Peltola et al i'994); one splicing defective mutation (Fisher and Aronson 1991b); and a deletion mutation of the C-terminal of GA (Jalanko et al 1994) --were further characterized biochemically.…”

Section: G C C a C T G G G A A T G G T G A T A T A T G A T G C G C mentioning

confidence: 97%

“…Approximately 3% of the population in certain areas of Finland carry this mutation (Aula et al 1982;Mononen et al 1991b), and it occurs in 98% of Finnish AGU patients who have been screened (Syvgnen et al 1992). Currently, 14 other AGU mutations also have been determined outside Finland (Ikonen et al 1991a;Mononen et al 1993;Peltola et al 1994;Jalanko et al 1995). The gene coding human GA consists of 9 exons spanning 13 kb (Park et al 1991) and has been chromosomally localized at 4q32-q33 (Morris et al 1992).…”

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confidence: 99%

Single base deletion in exon 7 of the glycosylasparaginase gene causes a mild form of aspartylglycosaminuria in a patient of Mauritian origin

Park

Rossiter

Fensom

et al. 1995

J of Inher Metab Disea

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Aspartylglycosaminuria (AGU) is a lysosomal storage disorder of glycoprotein degradation caused by deficiency of glycosylasparaginase (GA). A deletion mutation was found in a mildly affected AGU patient whose parents are first-cousins of Mauritian origin. One bp deletion at position 787 or 788 (delta T788) in exon 7 of the GA gene resulted in a frameshift and produced an immediate stop codon. The resulting truncated polypeptide was defective in its post-translational proteolytic processing and remained as a single chain (36 kDa) with no GA activity.

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Spectrum of mutations in aspartylglucosaminuria.

Cited by 50 publications

References 34 publications

Two mutations in Marfan syndrome resulting in truncated fibrillin polypeptides.

Two mutations in Marfan syndrome resulting in truncated fibrillin polypeptides.

Structural Basis of a Point Mutation that Causes the Genetic Disease Aspartylglucosaminuria

Single base deletion in exon 7 of the glycosylasparaginase gene causes a mild form of aspartylglycosaminuria in a patient of Mauritian origin

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