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  • 1995-1999  (5)
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  • 1995-1999  (5)
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  • 1
    ISSN: 1573-2665
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Metachromatic leukodystrophy (MLD) is an autosomal recessive disease of myelin metabolism caused by a deficiency in the lysosomal enzyme arylsulphatase A (ARSA). We have identified a new mutation in exon 4 of the ARSA gene of two unrelated Belgian patients with late-infantile MLD. The mutation predicts an aspartic acid-to-histidine substitution at position 255 in arylsulphatase A (D255H), in a highly conserved region among sulphatases. Transient expression of the mutation in COS cells did not show an increase in ARSA activity. Both patients were compound heterozygotes carrying the frequent splice site mutation in intron 2 (459+1G→A) on the other allele.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1432-1203
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract We have previously sequenced the complete coding region and the promoter region of the β-glucuronidase gene of a patient with mild mucopolysaccharidosis type VII (MPS VII) and identified a nonsense mutation in the gene inherited from her mother. The mutation inherited from her father was not found. Here, we have extended the sequence analysis of the introns to cover all putative lariat branch points and putative intronic enhancers, although no nucleotide changes have been found in these regions. Careful analysis of mRNA structure by reverse transcription/polymerase chain reaction (RT-PCR) and direct sequencing has revealed the inclusion of a new exon derived from an antisense Alu-repeat in intron 8 and the skipping of exon 9 in a large proportion of the mRNA of our patient. A 2-bp deletion creating a strong 5’-splice site has subsequently been identified in the paternal gene of the patient (IVS8+0.6kbdelTC). With a sensitive RT-PCR assay, we demonstrate that both the inclusion of the Alu-cassette and the skipping of exon 9 are minor events in control samples and that mRNA with both alterations is only found in the IVS8+0.6kbdelTC carrier. The increased proportion of exon 9 skipping seems to be related to the premature termination of translation. This is the third report of a human disease mutation that creates a splice site and activates an antisense Alu-cassette; the question rises as to how these apparently strong cryptic exons are generally excluded from coding sequences.
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  • 3
    ISSN: 1432-1203
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Mucopolysaccharidosis type VII (MPS VII, Sly syndrome) is an autosomal recessively inherited lysosomal storage disease caused by a deficiency in β-glucuronidase. We identified and studied a novel allele containing two C-to-T transitions resulting in P408S and P415L alterations, which is present in homozygous state in one Mexican patient and in heterozygous state in another. None of the previous reports describing mutations in the MPS VII gene include Mexican patients. Expression of either of the mutations individually showed only modest effects on the properties of the enzyme. However, expression of the doubly mutant allele resulted in markedly reduced activity and rapid degradation in an early biosynthetic compartment.
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  • 4
    ISSN: 1432-1203
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract We used polymerase chain reaction (PCR)/single-strand conformation polymorphism analysis and direct sequencing of the coding region of the β-glucuronidase cDNA and gene to detect mutations causing β-glucuronidase enzyme deficiency in five MPS VII patients. Four patients presented with hydrops fetalis, one with an early infantile form of the disease. Genetic heterogeneity of MPS VII alleles was further confirmed in this study. Recurrent mutations were observed in patients of related origin. Previously unknown alleles detected were R110X, F361Δ9, 1270 + 1G→A, S52F and 1480Δ4. Reverse transcription/PCR analysis of the 1270 + 1G→A messenger showed aberrant splicing: inclusion of intron 7 or skipping of exons 6–7 and 9. Messenger RNA transcribed from the R110X and 1480Δ4 alleles was unstable. We detected a 2154A/G change in the 3′ non-coding region of the gene, in the neighbourhood of the two consensus polyadenylation sites. 3′-Rapid amplification of cDNA ends/ PCR of fibroblast cDNA revealed equal usage of two alternative polyadenylation sites. The 2154A/G substitution did not influence adenylation-site choice, nor the amount of stable messenger produced. The finding that 2 out of 30 normal controls carried the 2154G allele indicated that the 2154A/G substitution is a harmless polymorphism. The S52F and F361Δ9 cDNAs were constructed in vitro and used to transfect COS cells transiently. Both mutations completely abolished enzyme activity.
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  • 5
    ISSN: 1432-1203
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Deficiency of β-glucuronidase is the cause of the human lysosomal storage disorder mucopolysaccharidosis type VII (MPS VII). The wide interfamilial variation in the presentation of this disorder complicates clinical diagnosis. Since greatly reduced β-glucuronidase enzyme activity may also be found in healthy individuals (pseudodeficiency), diagnosis based on the biochemical phenotype is also difficult. This is illustrated by the patients studied here, who had extremely mild symptoms confined to the spine, or tachycardia, or upper respiratory infection, and who had low β-glucuronidase activity, and excessive granulation of granulocytes and monocytes on routine blood smears. Low enzyme activity was caused by mutations in the β-glucuronidase gene in all cases. One patient was homozygous for the previously described D152N allele. Family information and 35SO4-uptake studies clearly demonstrated that he was pseudodeficient, with symptoms unrelated to his low β-glucuronidase activity. Two patients of another family were compound heterozygotes for a C38G and a Y626H allele, and were probably extremely mild MPS VII patients. The low β-glucuronidase activity in another mild MPS VII patient was due to reduced biosynthesis of stable mRNA from one allele, and a W446X mutation on the second. Extremely low β-glucuronidase enzyme activity was also found in the serum of a carrier of a 1801ΔT allele, possibly as a consequence of a dominant-negative effect. A combination of investigations is necessary in order to differentiate between mild disease and pseudodeficiency in individuals with enzyme activities close to the threshold.
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