Search PubMed⌕ Search

Biomedical subjects

P Aula

Publications and source records attributed to P Aula.

At least 19 recordsLinked to original sources
PubMed1995

Linkage disequilibrium utilized to establish a refined genetic position of the Salla disease locus on 6q14-q15.

Salla disease (SD), an inherited free sialic acid storage disorder, is caused by impaired transport of free sialic acid across the lysosomal membrane. Clinical characteristics of the disease include severe psychomotor retardation and some neurological abnormalities. We report here detailed linkage analyses of 50 Finnish SD families that localize the SD disease gene to a refined chromosomal area on 6q14-q15. The highest lod score of 17.30 was obtained with a microsatellite marker of locus D6S280. When linkage disequilibrium was adopted in the linkage analyses, we could further assign the SD locus to the immediate vicinity of marker locus D6S406. Linkage disequilibrium facilitated further restriction of the critical chromosomal region to approximately 80 kb, well within the limits of positional cloning techniques.

Alleles↗
PubMed1995

Identification of a novel mutation causing aspartylglucosaminuria reveals a mutation hotspot region in the aspartylglucosaminidase gene.

Aspartylglucosaminuria (AGU) is a recessively inherited metabolic disorder caused by the deficiency of a lysosomal enzyme, aspartylglucosaminidase. The worldwide most common mutation causing the disease is the AGUFin, enriched in Finland; all the other known AGU mutations are family-specific. We developed exon-specific primers to facilitate mutation search directly from the genomic DNA and identified a novel mutation, designated AGUFin minor, in seven Finnish AGUFin compound heterozygote patients. This deletion/frameshift mutation creates a premature translational termination codon and was shown to result in severely reduced transcript levels as quantified by the solid-phase minisequenching method. Genealogical data on this novel mutation suggest its relatively recent introduction into the population. The AGU mutations identified so far have been reported to be evenly distributed throughout the 1 kb coding region of the AGA cDNA. We identified a mutation hotspot region of 40 bp within the 12.5 kb AGA gene containing two previously identified mutations and the novel AGUFin minor mutation characterized in this study.

Acetylglucosamine↗
PubMed1995

Solid-phase minisequencing confirmed by FISH analysis in determination of gene copy number.

The solid-phase minisequencing method (Syvnen et al. 1990) allows accurate quantative determination of the ratio between two DNA or RNA sequences that are present as a mixture in a sample and differ from each other only by a single nucleotide. Here, we present another application of the minisequencing method, the determination of the gene copy number in a genome. The copy number of a marker gene aspartyl glucosaminidase (AGA) located at 4qter, was determined in three patients with a chromosomal alteration involving the distal region of 4q. For the minisequencing assay an equal amount of DNA from a patient homozygous for a mutation in the AGA gene was added to the DNA samples concerned. The relative amount of the normal sequence determined in each combined sample gives the copy number of the AGA gene. Fluorescence in situ hybridization (FISH), applied in parallel as a control, produced concordant results with solid-phase minisequencing in each case. As the potential of the minisequencing lies in automation, it could be a useful tool in the screening of monosomies, trisomies or loss of heterozygosity in diagnostics.

Aspartylglucosylaminase↗
PubMed1995

Lysosomal free sialic acid storage disorders with different phenotypic presentations--infantile-form sialic acid storage disease and Salla disease--represent allelic disorders on 6q14-15.

Similarities in biochemical findings have suggested that Salla disease (SD) and the infantile form of sialic acid storage disease (ISSD) could represent allelic disorders, despite their drastically different clinical phenotypes. SD and ISSD are both characterized by lysosomal storage of free N-acetyl neuraminic acid. However, in SD the increase detected in urine is 8-24-fold, whereas in ISSD the corresponding amount is 20-50-fold and patients are also more severely affected. Here we report linkage studies in 50 Finnish SD families and 26 non-Finnish families with no genealogical connections to Finns affected either with the Finnish type of SD, the "intermediate" form of the disease, or ISSD. All forms of the disease show linkage to the same locus on 6q14-q15. Haplotype analyses of Finnish SD chromosomes revealed one common haplotype, which was also seen in most of the non-Finnish patients with Finnish type of SD. This ancestral haplotype deviated from those observed in ISSD patients, who had a different common haplotype.

Alleles↗
PubMed1995

Attitudes toward genetic testing among the general population and relatives of patients with a severe genetic disease: a survey from Finland.

In the present study we explore the attitudes of the Finnish population toward genetic testing by conducting a questionnaire study of a stratified sample of the population as well as of family members of patients with a severe hereditary disease, aspartylglucosaminuria (AGU). The questionnaire evaluated attitudes toward gene tests in general and also respondents' preparedness to undergo gene tests for predictive testing, carrier detection, prenatal diagnosis, and selective abortion, in theoretical situations. The results of the study indicate that both the Finnish population in general and family members of AGU patients have a favorable attitude toward genetic testing. However, a commonly expressed reason against testing was that test results might lead to discrimination in employment or insurance policies. Based on the responses, we predict that future genetic testing programs will most probably be met with a high acceptance rate by the Finnish population.

Adolescent↗
PubMed1994

Transabdominal chorionic villus sampling and amniocentesis for prenatal diagnosis: 5 years' experience at a university centre.

The fetal loss rates and fetal congenital birth defects in 821 transabdominal (TA) chorionic villus sampling (CVS) and 771 amniocentesis (AC) cases were evaluated from a 5-year period (1987-1991) at the University Central Hospital of Turku. The parents were given the option of choosing between the two sampling procedures. CVS was performed, in most cases, at 11 weeks of gestation; and AC, at 15 weeks. The rate of total post-procedure loss was 6.7 per cent in the CVS group and 4.4 per cent in the AC group (p = 0.08). The rate of spontaneous abortions was 1.9 per cent in the CVS group and 1.0 per cent in the AC group (p = 0.10). The number of birth defects was low in both study groups. No limb reduction cases were observed. Mosaicism was noted in 14 CVS cases and in five AC cases. We conclude that TA-CVS is a safe and practical alternative to AC in prenatal fetal karyotyping.

Abdomen↗
PubMed1994

Phenotypic variation and magnetic resonance imaging (MRI) in Salla disease, a free sialic acid storage disorder.

Salla disease (SD) is a recessively inherited lysosomal storage disorder particularly common in the Finnish population. Patients with SD are normal at birth, but develop psychomotor delay and ataxia during the first year of life. Phenotypic variation of SD is wide, ranging from severely disabled children to mentally retarded adults capable of living under sheltered conditions. In the present study four unusually severely affected patients were investigated by detailed clinical examination, magnetic resonance imaging (MRI) and analysis of the excretion of free sialic acid in urine. MRI study, reported here for the first time, revealed a similarly defective myelination pattern in seven patients. The myelination process seemed to cessate at the level of an infant of a few months of age. Genetic linkage study of the families of the severely affected patients suggested linkage to the recently discovered SD locus on the long arm of chromosome 6. Locus heterogeneity therefore is an unlikely explanation of the phenotypic variation in SD.

Adolescent↗
PubMed1993

The spectrum of mitochondrial DNA mutations in families with Leber hereditary optic neuroretinopathy.

The mitochondrial complex I genes were sequenced in seven Leber hereditary optic neuroretinopathy (LHON) families without the ND4/11,778 and ND1/3460 mutations. Four replacement mutations restricted only to LHON families were found, one in the ND1 gene at nt 4025, and three in the ND5 gene at nt 12,811, 13,637, and 13,967. The mutations did not change evolutionarily conserved amino acids suggesting that they are not primary LHON mutations in these families. They may be considered as secondary LHON mutations serving as exacerbating factors in an appropriate genetic background. A complex III mutation, cyt b/15,257, has been suggested to be one of the primary mutations causing LHON. Its presence was determined for 23 Finnish LHON families, and it was detected in two families harboring the ND4/11,778 mutation. Similarly, complex IV mutation COI/7444 was screened in Finnish LHON families, and it was found in one family carrying the ND1/3460 mutation.

Amino Acids↗
PubMed1993

Prospects of carrier screening of aspartylglucosaminuria in Finland.

The frequency of carriers of the AGUFin mutation, the predominant mutation causing aspartylglucosaminuria in Finland, was determined in a population sample comprising 553 newborns from a delivery hospital in southern Finland, and 607 from a hospital in northern Finland. The AGUFin point mutation was identified from cord blood samples using the PCR-based, solid-phase minisequencing method. Nineteen carriers of the AGUFin mutation were detected, 8 (1:69) in the sample from the southern and 11 (1:55) from the northern population, respectively. The solid-phase minisequencing method proved to be rapid and convenient for the detection of the AGUFin mutation, and can readily be applied in large-scale carrier screening at the population level.

Amino Acid Metabolism, Inborn Errors↗
PubMed1992

Exclusion map of Salla disease: attempts to localize the disease gene using a computer program.

Salla disease is a lysosomal storage disorder due to impaired transport of free sialic acid across the lysosomal membrane. The clinical presentation of this autosomal recessive trait is severe psychomotor retardation from early infancy on. In order to determine the gene locus for the disease we have initiated a genetic linkage study using polymorphic gene markers in representative family material comprising about 60% of all families known to be affected with Salla disease. Here we present an exclusion map based on combined linkage data from 64 informative loci on 19 autosomes. Theoretically, at least 55% of the genome has been excluded as a locus for the disease gene, while some chromosome areas, particularly the long arm of chromosome 2, are highlighted as possible sites for the gene locus.

Chromosome Mapping↗
PubMed1992

Convenient and quantitative determination of the frequency of a mutant allele using solid-phase minisequencing: application to aspartylglucosaminuria in Finland.

Aspartylglucosaminuria (AGU) is a recessively inherited lysosomal disease caused by inadequate aspartylglucosaminidase (AGA) activity. The disease is prevalent in the genetically isolated Finnish population. We have used a new method, solid-phase minisequencing, to determine the frequency of two missense mutations in the AGA gene in this population. In samples from 70% of the Finnish AGU families, we found that the two nucleotide changes were always associated, and they were identified in 98% of the AGU alleles analyzed. Thus, the high prevalence of AGU in the Finnish population is the consequence of a founder effect of one ancient mutation. The identification of asymptomatic carriers by the minisequencing test proved to be unequivocal. The method also allowed quantification of a mutated nucleotide sequence present in less than 1% of a sample. The frequency of AGU carriers in this population was 1/36 when estimated by quantifying the mutated AGU allele in a pooled leukocyte sample from 1350 normal Finnish individuals.

Acetylglucosamine↗
PubMed1991

Spectrum of mutations in aspartylglucosaminuria.

Aspartylglucosaminuria (AGU) is an inherited lysosomal storage disorder caused by the deficiency of aspartylglucosaminidase. We have earlier reported a single missense mutation (Cys163----Ser) to be responsible for 98% of the AGU alleles in the isolated Finnish population, which contains about 90% of the reported AGU patients. Here we describe the spectrum of 10 AGU mutations found in unrelated patients of non-Finnish origin. Since 11 out of 12 AGU patients were homozygotes, consanguinity has to be a common denominator in most AGU families. The mutations were distributed over the entire coding region of the aspartylglucosaminidase cDNA, except in the carboxyl-terminal 17-kDa subunit in which they were clustered within a 46-amino acid region. Based on the character of the mutations, most of them are prone to affect the folding and stability and not to directly affect the active site of the aspartylglucosaminidase enzyme.

Acetylglucosamine↗
PubMed1991

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

We have isolated a 2.1 kb cDNA which encodes human aspartylglucosaminidase (AGA, E.C. 3.5.1.26). The activity of this lysosomal enzyme is deficient in aspartylglucosaminuria (AGU), a recessively inherited lysosomal accumulation disease resulting in severe mental retardation. The polypeptide chain deduced from the AGA cDNA consists of 346 amino acids, has two potential N-glycosylation sites and 11 cysteine residues. Transient expression of this cDNA in COS-1 cells resulted in increased expression of immunoprecipitable AGA protein. Direct sequencing of amplified AGA cDNA from an AGU patient revealed a G----C transition resulting in the substitution of cysteine 163 with serine. This mutation was subsequently found in all the 20 analyzed Finnish AGU patients, in the heterozygous form in all 53 carriers and in none of 67 control individuals, suggesting that it represents the major AGU causing mutation enriched in this isolated population. Since the mutation produces a change in the predicted flexibility of the AGA polypeptide chain and removes an intramolecular S-S bridge, it most probably explains the deficient enzyme activity found in cells and tissues of AGU patients.

Amino Acid Sequence↗
PubMed1991

Confirmation of the chromosomal localization of human lamp genes and their exclusion as candidate genes for Salla disease.

Salla disease is an inherited lysosomal storage disorder caused by accumulation of free sialic acid in the lysosomes. Lamp genes, lamp A and lamp B (lysosome associated membrane proteins), are the first known genes encoding for human lysosomal membrane proteins. Absence of linkage in a large group of families shows that lamp genes are not involved in Salla disease. The lamp genes were localized, using Southern hybridization in hamster--human hybrid cell panels, to chromosomes 13 (lamp A) and X (lamp B).

Antigens, CD↗
PubMed1991

Sialic acid storage disorders: observations on clinical and biochemical variation.

Lysosomal accumulation of free sialic acid results in two phenotypically distinct inherited metabolic disorders, Salla disease and infantile sialic acid storage disease. Clinical and biochemical findings in both diseases are reviewed. Recent studies indicate that sialic acid storage is a consequence of defective function of a lysosomal membrane transport system specific for sialic acid and some other acidic monosaccharides.

Adult↗