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P Aula

Publications and source records attributed to P Aula.

At least 37 records · Page 2Linked to original sources
PubMed1997

Tissue distribution of the ND4/11778 mutation in heteroplasmic lineages with Leber hereditary optic neuropathy.

Leber hereditary optic neuropathy (LHON) is a maternally inherited eye disease most commonly caused by mitochondrial DNA (mtDNA) point mutation at position 11778, 3460, or 14484. Approximately 14% of families show heteroplasmy for the pathogenic mutations but little is known about the mutational burden in different tissues of these heteroplasmic individuals. Consequently, estimating the risks of visual loss is difficult. This study presents quantitative mutation analyses of tissues representing all embryonal layers in two families heteroplasmic for the 11778 mutation. These analyses show that a high amount of mutated mtDNA in leukocytes is correlated with a high proportion of mutated mtDNA in other tissues.

DNA, Mitochondrial↗
PubMed1997

Human cationic amino acid transporter gene hCAT-2 is assigned to 8p22 but is not the causative gene in lysinuric protein intolerance.

Lysinuric protein intolerance (LPI) is a recessively inherited amino acid disorder characterized by defective efflux of cationic amino acids at the basolateral membrane of the intestinal and renal tubular epithelium. Recently, cDNAs encoding the related proteins hCAT-2A and hCAT-2B have been cloned. These two carrier proteins are most likely to product of the same gene, hCAT-2. Using the hCAT-2B cDNA, we assigned the hCAT-2 gene to chromosome 8p22. Furthermore, by linkage analysis in Finnish LPI families, we ruled out that hCAT-2B is involved in LPI disease.

Amino Acid Metabolism, Inborn Errors↗
PubMed1997

Screening for connexin 32 mutations in Charcot-Marie-Tooth disease families with possible X-linked inheritance.

The X-linked dominant form of Charcot-Marie-Tooth disease (CMTX) is associated with mutations in a gene coding for the gap-junction protein connexin 32 (Cx32). We screened 32 CMT families with a pedigree pattern suggestive of X-linked inheritance for the presence of mutations in the coding region of Cx32 by direct sequencing. Five of the families had a CMT1 diagnosis, 24 had a CMT2 diagnosis and 3 patients had an unspecified CMT. Eight families with a Cx32 point mutation were detected. Five different mutations (four of them published previously) were found in six CMT2 families and one mutation was found in a sporadic CMT1 male patient. One of the mutations, Met194Val, is among the first described in the fourth transmembrane domain of Cx32. Two CMT2 families and the sporadic CMT1 patient had the same mutation, Arg22Gln. An additional, previously unpublished mutation, Arg75Trp, was found in a male patient with unspecified CMT, who subsequently was verified to have a variant Klinefelter syndrome with 48,XXYY karyotype. Our findings show the difficulty in distinguishing CMTX patients from CMT1 and CMT2 patients, and they emphasize the need for Cx32 mutation screening in families previously diagnosed with CMT2.

Charcot-Marie-Tooth Disease↗
PubMed1997

Epidemiology of hereditary neuropathy with liability to pressure palsies (HNPP) in south western Finland.

An epidemiological study of hereditary neuropathy with liability to pressure palsies (HNPP) was carried out in south western Finland, with a population of 435,000. The diagnosis was established in 69 patients from 23 unrelated families through family and medical history, clinical neurological and neurophysiological examinations and with documentation of the deletion at gene locus 17p11.2 in at least one member of each family. This gave a prevalence of at least 16/100,000, which is remarkably high. However, due to the insidious nature of HNPP, most probably it is still an underestimation. This is the first population-based prevalence figure reported for HNPP. The prevalence is somewhat lower than that obtained for CMT in the same population, which agrees with the proposal that HNPP and CMT 1A are reciprocal products of the same unequal crossing-over. The clinical pictures of our patients were, in general, similar to those previously described in HNPP.

Adolescent↗
PubMed1997

Improved prenatal diagnosis of the congenital nephrotic syndrome of the Finnish type based on DNA analysis.

Haplotype analysis and alpha-fetoprotein quantitation comprise a prenatal diagnosis of congenital nephrosis. Congenital nephrotic syndrome of the Finnish type (CNF) is an autosomal recessive disease characterized by massive proteinuria and nephrotic syndrome from birth. Prenatal diagnosis of CNF has previously been based on the quantitation of alpha-fetoprotein (AFP) in the amniotic fluid and maternal serum, but an increased AFP is not specific for the disease. We have recently localized the CNF gene to the chromosome 19q13.1 region and observed a strong linkage disequilibrium to the genetic markers D19S610, D19S608, D19S224 and D19S220 in this chromosomal area. Four main CNF-haplotypes have been observed in Finnish kindreds. In the present study, linkage and haplotype analyses have been applied to prenatal diagnosis of six families with a history of CNF. The results diminish the risk of false positive diagnosis and abortions of healthy fetuses in families at risk.

Amniotic Fluid↗
PubMed1997

Lysinuric protein intolerance (LPI) gene maps to the long arm of chromosome 14.

Lysinuric protein intolerance (LPI) is an autosomal recessive disease characterized by defective transport of cationic amino acids and by hyperammonemia. Linkage analysis in 20 Finnish LPI families assigned the LPI gene locus to the proximal long arm of chromosome 14. Recombinations placed the locus between framework markers D14S72 and MYH7, a 10-cM interval in which the markers D14S742, D14S50, D14S283, and TCRA showed no recombinations with the phenotype. The phenotype was in highly significant linkage disequilibrium with markers D14S50, D14S283, and TCRA. The strongest allelic association obtained with marker TCRA, resulting in a P(excess) value of .98, suggests that the LPI gene locus lies in close proximity to this marker, probably within a distance of < 100 kb.

Adult↗
PubMed1997

Two novel mutations in a Canadian family with aspartylglucosaminuria and early outcome post bone marrow transplantation.

Aspartylglucosaminuria (AGU) is a lysosomal storage disease caused by deficiency of aspartylglucosaminidase. The disease is overrepresented in the Finnish population, in which one missense mutation (Cys163Ser) is responsible for 98% of the disease alleles. The few non-Finnish cases of AGU which have been analyzed at molecular level have revealed a spectrum of different mutations. Here, we report two new missense mutations causing AGU in two Canadian siblings. The patients were compound heterozygotes with a G299-->A transition causing a Gly100-->Gln substitution and a T404-->C transition resulting in a Phe135-->Ser change in the cDNA coding for aspartylglucosaminidase. The younger patient recently underwent bone marrow transplantation.

Acetylglucosamine↗
PubMed1996

A physical map of the 6q14-q15 region harboring the locus for the lysosomal membrane sialic acid transport defect.

Two phenotypic presentations of excessive accumulation of free sialic acid in lysosomes, Salla disease and infantile sialic acid storage disease, have been assigned to the same locus at 6q14-q15. Here we have restricted the critical DNA region by analyses of extended haplotypes and constructed a long-range physical contig over the critical 200-kb chromosomal region flanked by the markers D6S280 and D6S1622. The efficient fiber-FISH technique was applied to order and orient the clones, and this facilitated avoidance of the tedious restriction mapping by pulsed-field gel electrophoresis. We excluded all seven known ESTs and nine cDNAs assigned to this DNA region and tentatively identified two potential CpG islands within the region, which now represent positional candidate genes for the sialic acid storage disorders.

Chromosomes, Human, Pair 6↗
PubMed1996

A de novo duplication in 17p11.2 and a novel mutation in the Po gene in two Déjérine-Sottas syndrome patients.

Déjérine-Sottas syndrome (DSS), or hereditary motor and sensory neuropathy (HMSN) type III, is a severe hypertrophic demyelinating neuropathy with infantile onset. The clinical symptoms are similar to those found in Charcot-Marie-Tooth disease type 1 (CMT1) or HMSN type I patients, but they are more severe. DSS is genetically heterogeneous. Dominant mutations in two major peripheral myelin protein genes, PMP22 and Po, are associated with a DSS phenotype. Mutations in the same genes are also responsible for the CMT1 phenotype. A 1.5-Mb duplication in 17p11.2 is the major mutation found in familial and sporadic CMT1 patients. We studied two genetically sporadic DSS patients. The presence of a de novo duplication in one patient was revealed by Southern blot analysis, using polymorphic markers located in the duplicated area. The 17p11.2 allele segregation in this patient and in her parents suggests that the duplication is of maternal origin. In the other patient, single-strand conformation polymorphism (SSCP) analysis of the 6 exons of the Po gene revealed two additional bands in exon 3. Sequencing of this exon identified a novel dominant mutation replacing a sequence of 8 bp by a mutated sequence of 5 bp. The mutation apparently leads to the replacement of 4 amino acids at positions 86-89 by three different amino acids, in an area that is part of a predicted beta-strand. Our findings support the suggestion that DSS and CMT1 disease should not be considered as two different clinical entities.

Adult↗
PubMed1996

Haplotype analysis in prenatal diagnosis and carrier identification of Salla disease.

Salla disease (SD) is an autosomal recessive disorder in which free sialic acid (N-acetyl neuraminic acid) accumulates in lysosomes. A specific transport mechanism for acidic monosaccharides on the lysosomal membrane has recently been described, but the molecular deficiency causing SD is still unknown. We have previously mapped the SD gene to 6q14-q15 by means of genetic linkage analysis and restricted the positive chromosomal area to less than 100 kb with linkage disequilibrium mapping. The two best allelic association markers have now retrospectively been used in five prenatal analyses originally studied with sialic acid assays in chorionic villus specimens. In four cases an unaffected fetus was predicted with a probability level of more than 94%, which was in concordance with the biochemical data. One fetus was predicted to be affected with over 96% probability, as was shown by free sialic acid assays in a CVS sample and in fetal tissues after termination of the pregnancy. Risk calculations incorporating disequilibrium were also used to predict the carrier status in members of six families with previous SD cases, and also in a few cases with no known family history of SD. DNA marker based analysis thus provides a reliable method for risk estimations in prenatal cases and for carrier identification of SD.

Adult↗
PubMed1996

The genetic relationship between the Finns and the Finnish Saami (Lapps): analysis of nuclear DNA and mtDNA.

The genetic relationships between two Finno-Ugric-speaking populations, the Finns and the Finnish Saami (Lapps), were studied by using PCR for six nuclear-DNA marker loci, mitochondrial restriction-site polymorphism, and sequence variation of a 360-bp segment of the mitochondrial control region. The allele frequencies of each of the nuclear-DNA marker loci and the frequencies of mtDNA restriction haplotypes were significantly different between the populations. The Saami showed exceptionally low variation in their mtDNA restriction sites. The 9-bp deletion common in East Asian populations was not observed, nor did the haplotype data fit into the haplogroup categorization of Torroni et al. The average number of nucleotide substitutions from the mtDNA haplotype data indicated that the Finnish Saami may be closer to the Finns than to the other reference populations, whereas nuclear DNA suggested that the Finns are more closely related to the European reference populations than to the Finnish Saami. The similarity of the Finns to the other Europeans was even more pronounced according to the sequence data. We were unable to distinguish between the Finns and either the Swiss or Sardinian reference populations, whereas the Finnish Saami clearly stood apart. The Finnish Saami are distinct from other Circumarctic populations, although two of the lineages found among the Saami showed closer relationship to the Circumarctic than to the European lineages. The sequence data indicated an exceptionally high divergence for the Saami mtDNA control lineages. The distribution of the pairwise nucleotide differences in the Saami suggested that this population has not experienced an expansion similar to what was indicated for the Finns and the reference populations.

Base Sequence↗
PubMed1996

DNA-based carrier screening in primary healthcare: screening for aspartylglucosaminuria mutations in maternity health offices.

Large-scale genetic screening programs are complex enterprises in which ethical, technical, medical, and socioeconomic aspects have to be handled with professional expertise. Establishment of automated, relatively robust, and inexpensive laboratory techniques is one step of this path. Here a pilot carrier-screening program for the mutations causing aspartylglucosaminuria was carried out for pregnant women in primary care maternity health offices. Women (1975) were tested before their 12th week of pregnancy, and 31 heterozygotes were detected. The sampling was based on dried blood strips, facilitating convenient handling and inexpensive mailing to the laboratory. The mutation detection technique, solid-phase mini-sequencing simplified by the use of scintillation microplates and automated equipment, proved to be rapid, simple, inexpensive, and reliable, with a low repeat rate (2.5%). In conclusion, we found that good collaboration between the primary healthcare unit, the laboratory, and counseling experts, combined with modern laboratory technology, facilitate reliable low-cost genetic testing.

Acetylglucosamine↗
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

Genes and languages in Europe: an analysis of mitochondrial lineages.

When mitochondrial DNA sequence variation is analyzed from a sample of 637 individuals in 14 European populations, most populations show little differentiation with respect to each other. However, the Saami distinguish themselves by a comparatively large amount of sequence difference when compared with the other populations, by a different distribution of sequence diversity within the population, and by the occurrence of particular sequence motifs. Thus, the Saami seem to have a long history distinct from other European populations. Linguistic affiliations are not reflected in the patterns of relationships of mitochondrial lineages in European populations, whereas prior studies of nuclear gene frequencies have shown a correlation between genetic and linguistic evolution. It is argued that this apparent contradiction is attributable to the fact that genetic lineages and gene frequencies reflect different time perspectives on population history, the latter being more in concordance with linguistic evolution.

Base Sequence↗
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↗