Biomedical subjects

L Peltonen

Publications and source records attributed to L Peltonen.

At least 73 records · Page 4Linked to original sources

PubMed2000

Use of population isolates for mapping complex traits.

Geneticists have repeatedly turned to population isolates for mapping and cloning Mendelian disease genes. Population isolates possess many advantages in this regard. Foremost among these is the tendency for affected individuals to share ancestral haplotypes derived from a handful of founders. These haplotype signatures have guided scientists in the fine mapping of scores of rare disease genes. The past successes with Mendelian disorders using population isolates have prompted unprecedented interest among medical researchers in both the public and private sectors. Despite the obvious genetic and environmental complications, geneticists have targeted several population isolates for mapping genes for complex diseases.

Animals↗

PubMed2000

Loss-of-function mutations in TYROBP (DAP12) result in a presenile dementia with bone cysts.

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL; MIM 221770), also known as Nasu-Hakola disease, is a recessively inherited disease characterized by a combination of psychotic symptoms rapidly progressing to presenile dementia and bone cysts restricted to wrists and ankles. PLOSL has a global distribution, although most of the patients have been diagnosed in Finland and Japan, with an estimated population prevalence of 2x10-6 (ref. 2) in the Finns. We have previously identified a shared 153-kb ancestor haplotype in all Finnish disease alleles between markers D19S1175 and D19S608 on chromosome 19q13.1 (refs 5,6). Here we characterize the molecular defect in PLOSL by identifying one large deletion in all Finnish PLOSL alleles and another mutation in a Japanese patient, both representing loss-of-function mutations, in the gene encoding TYRO protein tyrosine kinase binding protein (TYROBP; formerly DAP12). TYROBP is a transmembrane protein that has been recognized as a key activating signal transduction element in natural killer (NK) cells. On the plasma membrane of NK cells, TYROBP associates with activating receptors recognizing major histocompatibility complex (MHC) class I molecules. No abnormalities in NK cell function were detected in PLOSL patients homozygous for a null allele of TYROBP.

Adaptor Proteins, Signal Transducing↗

PubMed2000

Linkage disequilibrium in isolated populations: Finland and a young sub-population of Kuusamo.

Linkage disequilibrium (LD), non-random association of alleles at closely linked chromosomal loci, has been used as a tool in the identification of disease alleles, and this has led to an improved understanding of pathology in many monogenic Mendelian human diseases. We are currently moving from the mapping and identification of monogenic disease loci to attempts at identifying loci involved in predisposition to multifactorial diseases. In the selection of ascertainment strategies in the studies of these complex diseases, the extent of background LD in different populations is an important consideration. Here, we compare the extent of LD among the alleles of linked loci in a randomly ascertained sample of individuals from the Finnish population and a set of individuals ascertained from the region of Kuusamo, a small sub-population, founded some 13 generations ago, which has experienced very little subsequent immigration. Thirty-three microsatellite loci were genotyped in chromosomal regions on 13q, 19q, 21q, Xq, and Xp. The genetic diversity of these loci was determined separately in the general Finnish sample and in the Kuusamo sample. The X-chromosomal loci are characterised by higher levels of LD in the samples from Kuusamo than in the much larger (and older) general population of Finland, whereas in alleles of autosomal loci very little LD was seen in either of these two samples.

Alleles↗

PubMed2000

Analysis of autism susceptibility gene loci on chromosomes 1p, 4p, 6q, 7q, 13q, 15q, 16p, 17q, 19q and 22q in Finnish multiplex families.

The role of genetic factors in the etiology of the autistic spectrum of disorders has clearly been demonstrated. Ten chromosomal regions, on chromosomes 1p, 4p, 6q, 7q, 13q, 15q, 16p, 17q, 19q and 22q have potentially been linked to autism.1-8 We have analyzed these chromosomal regions in a total of 17 multiplex families with autism originating from the isolated Finnish population by pairwise linkage analysis and sib-pair analysis. Mild evidence for putative contribution was found only with the 1p chromosomal region in the susceptibility to autism. Our data suggest that additional gene loci exist for autism which will be detectable in and even restricted to the isolated Finnish population.

Adolescent↗

PubMed2000

Mutations in the AIRE gene: effects on subcellular location and transactivation function of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy protein.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a monogenic autosomal disease with recessive inheritance. It is characterized by multiple autoimmune endocrinopathies, chronic mucocutaneous candidiasis, and ectodermal dystrophies. The defective gene responsible for this disease was recently isolated, and several different mutations in the novel gene, AIRE, have been identified, by us and by others, in patients with APECED. We have shown that the APECED protein is mainly localized, both in vitro and in vivo, to the cell nucleus, where it forms distinct speckles. This accords with the predicted structural features of the protein, which suggest involvement of AIRE in the regulation of gene transcription. Here, we report the results of mutational analyses of a series of 112 patients with APECED who were from various ethnic backgrounds. A total of 16 different mutations, covering 91% of disease alleles, were observed; of these, 8 were novel. The mutations are spread throughout the coding region of AIRE, yet four evident mutational hotspots were observed. In vitro expression of four different naturally occurring nonsense and missense mutations revealed a dramatically altered subcellular location of the protein in cultured cells. Interestingly, the wild-type APECED protein tethered to the Gal4 DNA-binding domain acted as a strong transcriptional activator of reporter genes in mammalian cells, whereas most of the analyzed mutant polypeptides had lost this capacity.

Alleles↗

PubMed2000

Assignment of a novel locus for autosomal recessive congenital ichthyosis to chromosome 19p13.1-p13.2.

Autosomal recessive congenital ichthyosis (ARCI) is a rare, clinically and genetically heterogeneous genodermatosis. One gene (transglutaminase 1, on 14q11) and one additional locus (on 2q33-35, with an unidentified gene) have been shown to be associated with a lamellar, nonerythrodermic type of ARCI. We performed a genomewide scan, with 370 highly polymorphic microsatellite markers, on five affected individuals from one large Finnish family with nonerythrodermic, nonlamellar ARCI. The only evidence for linkage emerged from markers in a 6.0-cM region on chromosome 19p13.1-2. The maximum two-point LOD score of 7.33 was obtained with the locus D19S252, and multipoint likelihood calculations gave a maximum location score of 5.2. The affected individuals share two common core haplotypes, which makes compound heterozygosity possible. The novel disease locus is the third locus linked to ARCI, supporting previous evidence for genetic heterogeneity of ARCI. This is also the first locus for a nonlamellar, nonerythrodermic phenotype of ARCI.

Child↗

PubMed2000

Genome-wide scan of predisposing loci for increased diastolic blood pressure in Finnish siblings.

OBJECTIVES: To review, on a genome-wide scale, a linkage result obtained in an earlier candidate gene analysis in this same study sample, and to look for other possible contributing genetic loci predisposing to hypertension in this population. DESIGN: An affected sibpair linkage study with highly polymorphic genetic markers spanning the genome at an average intermarker density of 10 cM. PARTICIPANTS: A total of 47 families with two affected siblings (mostly dizygotic twins) and all available additional family members from the genetic isolate of Finland. The families were identified through the Finnish Twin Cohort Study, the total number of this follow-up cohort being 13,888. The study sample was selected on the basis of early-onset hypertension with minimal presence of other phenotypic risk factors such as obesity. RESULTS: The AT1 locus stood out as the most significant locus in this population (maximum likelihood score 4.04). Some evidence for linkage was also detected with markers on chromosomes 2q (maximum likelihood score 2.96), 22q (2.07), and Xp (2.41). CONCLUSIONS: Our results establish the role of the AT1 locus, on a genome-wide scale, as a major contributing locus to essential hypertension in this study sample.

Blood Pressure↗

PubMed2000

A system for specific, high-throughput genotyping by allele-specific primer extension on microarrays.

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 3'-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.

Alleles↗

PubMed2000

Genome-wide scan of obesity in Finnish sibpairs reveals linkage to chromosome Xq24.

Obesity is a multifactorial trait with evidence of a genetic component. Obesity is very common in all westernized countries, including Finland, where 10% of the adult population has a body mass index of 32 kg/m2 or more. Here we report results from a three-stage genome-wide scan of obesity in 188 affected subjects (body mass index, > or =32 kg/m2) from 87 Finnish families. Initially, 374 markers with an average density of 10 centimorgans were genotyped. The strongest evidence for linkage to obesity was detected on chromosome Xq24, with the marker DXS6804 providing a maximum likelihood score (MLS) 3.14 in a model-free 2-point sibpair analysis. Fine-mapping in an extended sample set of 367 affected subjects from 166 families yielded a multipoint MLS of 3.48 over this X-chromosomal region. The Xq24 region contains a plausible candidate gene, serotonin 2C receptor, variants of which have been shown to predispose to obesity and type II diabetes in mice. Another chromosomal region also provided suggestive evidence of linkage, an area on 18q21, flanking the melanocortin-4 receptor, where a 2-point MLS of 2.42 with marker D18S1155 was obtained with a set of 367 affected subjects. In conclusion, our results in this Finnish study sample suggest that a locus on chromosome Xq24 influences the risk of obesity.

Adult↗

PubMed2000

Plasminogen activator inhibitor-1 (PAI-1) 4G/5G polymorphism, coronary thrombosis, and myocardial infarction in middle-aged Finnish men who died suddenly.

High plasminogen activator inhibitor-1 (PAI-1) plasma levels increase future risk of myocardial infarction (MI). The 4G allele of the 4G/5G polymorphism of the PAI-1 gene has been associated with increased plasma levels of PAI-1. The association of the PAI-1 polymorphism with coronary narrowings, coronary thrombosis and myocardial infarction (MI) was studied in a prospective autopsy series of 300 middle-aged Caucasian Finnish men (33 to 69 yrs) suffering sudden out-of-hospital death (Helsinki Sudden Death Study). The 4G allele was found in 76.8% of men with sudden cardiac death (SCD) compared to 67.5% in men who died accidentally and 63.2% in men who died of other diseases (p = 0.08 and p = 0.055, respectively). Men possessing the 4G allele had more often acute MI (OR 3.5; p <0.05) and coronary thrombosis (OR 5.5. p = 0.01) compared to 5G homozygotes. 5G homozygotes, comprising one third of the men in our study, seem to be at a decreased risk of thrombosis, whereas carriers of the common 4G allele have an increased risk of thrombosis, AMI and possibly SCD compared to 5G homozygotes.

Accidents↗

PubMed2000

Acute intermittent porphyria: expression of mutant and wild-type porphobilinogen deaminase in COS-1 cells.

BACKGROUND: Acute intermittent porphyria (AIP) is an autosomal dominant disorder that results from the partial deficiency of porphobilinogen deaminase (PBGD) in the heme biosynthetic pathway. Patients with AIP can experience acute attacks consisting of abdominal pain and various neuropsychiatric symptoms. Although molecular biological studies on the porphobilinogen deaminase (PBGD) gene have revealed several mutations responsible for AIP, the properties of mutant PBGD in eukaryotic expression systems have not been studied previously. MATERIALS AND METHODS: Seven mutations were analyzed using transient expression of the mutated polypeptides in COS-1 cells. The properties of mutated polypeptides were studied by enzyme activity measurement, Western blot analysis, pulse-chase experiments, and immunofluorescence staining. RESULTS: Of the mutants studied, R26C, R167W, R173W, R173Q, and R225X resulted in a decreased enzyme activity (0-5%), but R225G and 1073delA (elongated protein) displayed a significant residual activity of 16% and 50%, respectively. In Western blot analysis, the polyclonal PBGD antibody detected all mutant polypeptides except R225X, which was predicted to result in a truncated protein. In the pulse-chase experiment, the mutant polypeptides were as stable as the wild-type enzyme. In the immunofluorescence staining both wild-type and mutant polypeptides were diffusely dispersed in the cytoplasm and, thus, no accumulation of mutated proteins in the cellular compartments could be observed. CONCLUSIONS: The results confirm the causality of mutations for the half normal enzyme activity measured in the patients' erythrocytes. In contrast to the decreased enzyme activity, the majority of the mutations produced a detectable polypeptide, and the stability and the intracellular processing of the mutated polypeptides were both comparable to that of the wild-type PBGD and independent of the cross-reacting immunological material (CRIM) class.

Amino Acid Substitution↗

PubMed1999

Characterization of the human glutamate receptor subunit 3 gene (GRIA3), a candidate for bipolar disorder and nonspecific X-linked mental retardation.

The X-chromosome breakpoint in a female patient with a balanced translocation t(X;12)(q24;q15), bipolar affective disorder and mental retardation was mapped within the glutamate receptor 3 (GRIA3) gene by fluorescence in situ hybridization. The GRIA3 cDNA of 5894 bp was cloned, and the gene structure and pattern of expression were determined. The most abundant GRIA3 transcript is composed of 17 exons. An additional 5 exons (2a, 2b, 5a, 5b, and 5c) from the 5' end of the GRIA3 open reading frame were identified by EST analysis (ESTs AI379066 and AA947914). Two new polymorphic microsatellite repeats, (TC)(n=12-26) and (AC)(n=15-19), were identified within GRIA3 5' and 3'UTRs. No mutations were detected in families segregating disorders mapping across GRIA3, one with X-linked bipolar affective disorder (BP) and one with a nonspecific X-linked mental retardation (MRX27). To assess the possibility of the involvement of the GRIA3 gene in familial cases of complex BP, a large set of 373 individuals from 40 pedigrees segregating BP were genotyped using closely linked (DXS1001) and intragenic (DXS1212 and GRIA3 3' UTR (AC)(n))) GRIA3 STR markers. No evidence of linkage was found by parametric Lod score analysis (the highest Lod score was 0. 3 at DXS1212, using the dominant transmission model) or by affected sib-pair analysis.

Adult↗

PubMed1999

Developmental expression of palmitoyl protein thioesterase in normal mice.

Deficiency in palmitoyl protein thioesterase (PPT) results in the rapid death of neocortical neurons in human. Very little is known about the developmental and cell-specific expression of this lysosomal enzyme. Here we show that PPT is expressed as a major 2.65 kb and a minor 1.85 kb transcript in the mouse brain. Transcript levels gradually increase between postnatal days 10 and 30. In situ hybridization analysis revealed that PPT transcripts are found widely but not homogeneously in the brain. The most intense signal was detected in the cerebral cortex (layers II, IV-V), hippocampal CA1-CA3 pyramidal cells, dentate gyrus granule cells and the hypothalamus. Immunostaining of PPT was localized in the cell soma, axons and dendrites, especially in the pyramidal and granular cells of the hippocampus, correlating well, both spatially and temporally, with the immunoreactivity of a presynaptic vesicle membrane protein, synaptophysin. In whole embryos, at embryonic day 8, the PPT mRNA expression was most apparent throughout the neuroepithelium, and from day 9 onwards it was seen in all tissues. The expression pattern of PPT suggests its general significance for the brain cells and reflects the response to maturation and growth of the neural networks. Strong PPT immunoreactivity in the axons and dentrites would imply that PPT may not be exclusively a lysosomal enzyme. A notable correlation with synaptophysin would suggest that PPT may have a role in the function of the synaptic machinery.

Aging↗

PubMed1999

Functional consequences of amyloidosis mutation for gelsolin polypeptide -- analysis of gelsolin-actin interaction and gelsolin processing in gelsolin knock-out fibroblasts.

Gelsolin, an actin-modulating protein, derived from a single gene exists in intracellular and secreted forms. A point mutation at position 187 of both forms of gelsolin causes familial amyloidosis of the Finnish type (FAF). Here, we expressed both isoforms of the wild-type and FAF mutant gelsolin in mouse embryonic gelsolin-null fibroblasts. We demonstrate that the FAF mutation does not interfere with the normal actin-modulating function of intracellular gelsolin, and that aberrant processing of secreted FAF gelsolin to FAF amyloid precursor takes place in the gelsolin-negative background. These results suggest that, in patients with FAF, symptoms are caused by the accumulation in their tissues of amyloid derived from plasma gelsolin and are not due to functional differences in cytoplasmic gelsolin.

Actins↗

PubMed1999

Characterization of a novel gene, PNUTL2, on human chromosome 17q22-q23 and its exclusion as the Meckel syndrome gene.

We assigned two human expressed sequence tags (ESTs), WI-15444 and SGC32067, homologous to mouse brain protein h5, to the critical region for Meckel syndrome (MKS) on 17q22-q23. For the sequence analyses in MKS patients, we isolated the corresponding human gene, PNUTL2, by analyzing an Image cDNA clone that contained these ESTs. Based on sequence homologies, the gene belongs to an expanding family of GTP-binding proteins, septins, that are involved in cytokinesis. In Northern analysis, PNUTL2 is ubiquitously expressed as a 1.7-kb transcript in adult and fetal tissues with particularly high expression in the heart, liver, and adrenal gland. Mutation analysis using sequencing of RT-PCR products and Northern blot analysis in MKS patients exclude PNUTL2 as the gene for MKS.

Abnormalities, Multiple↗

PubMed1999

Positional cloning of the CLN5 gene defective in the Finnish variant of the LINCL.

Neuronal ceroid lipofuscinoses (NCLs) in children are progressive encephalopathies inherited as autosomal recessive traits. Progressive neuronal damage leads to psychomotor deterioration, visual failure, seizures, and finally to premature death. Based on the clinical course of the disease, the childhood forms can be divided into several subtypes. A variant form of the late infantile NCL (vLINCL), characterized by mental retardation, visual failure, ataxia, myoclonia, and death between the ages of 13 and 30 years, is prevalent in Finland. Information on ancient recombination events in disease alleles rising from this isolated population provided an efficient tool for refining the initial assignment of the CLN5 locus. Here we describe the steps resulting in the identification of the novel gene, defective in vLINCL.

Blotting, Northern↗

PubMed1999

Toward understanding the neuronal pathogenesis of aspartylglucosaminuria: expression of aspartylglucosaminidase in brain during development.

The deficiency of a lysosomal enzyme, aspartylglucosaminidase, results in a lysosomal storage disorder, aspartylglucosaminuria, manifesting as progressive mental retardation. To understand tissue pathogenesis and disease progression we analyzed the developmental expression of the enzyme, especially in brain, which is the major source of the pathological symptoms. Highest mRNA levels in brain were detected during embryogenesis, the levels decreased neonatally and started to increase again from Day 7 on. In Western analyses, a defective processing of aspartylglucosaminidase was observed in brain as compared to other tissues, resulting in very low levels of the mature, active form of the enzyme. Interestingly immunohistochemical analyses of mouse brain revealed that aspartylglucosaminidase immunoreactivity closely mimicked the myelin basic protein immunostaining pattern. The only evident neuronal staining was observed in the developing Purkinje cells of the cerebellum from Days 3 to 10, reflecting well the mRNA expression. In human infant brain, the immunostaining was also present in myelinated fibers as well as in the Purkinje cells and, additionally, in the soma and extensions of other neurons. In the adult human brain neurons and oligodendrocytes displayed immunoreactivity whereas myelinated fibers were not stained. Our results of aspartylglucosaminidase immunostaining in myelinated fibers of infant brain might imply the involvement of aspartylglucosaminidase in the early myelination process. This is consistent with previous magnetic resonance imaging findings in the brains of aspartylglucosaminuria patients, revealing delayed myelination in childhood.

Adult↗

PubMed1999

Association of FXIII Val34Leu with decreased risk of myocardial infarction in Finnish males.

Factor XIII is a transglutaminase that crosslinks fibrin in the last steps of the coagulation process. A few polymorphic sites have been identified in this gene, one of them being a point mutation (FXIII Val34Leu), leading to an amino acid change of valine to leucine. Recently, in British patients, FXIII 34Leu allele was suggested to be associated with a decreased incidence of myocardial infarction (MI). PAI-1 4G/4G genotype seemed to lessen the beneficial effect of FXIII 34Leu allele. The aim of our study was to further investigate the possible protective role of the FXIII 34Leu allele against MI and its suggested interaction with the PAI-1 4G/5G polymorphism. We carried out genotype analyses for FXIII Val34Leu using solid-phase minisequencing in two independent Finnish study groups. In our study, the FXIII 34Leu allele was associated with a lower risk of MI (P = 0.009), however, the PAI-1 4G allele showed no interaction with this polymorphism. To establish the population frequency of the FXIII 34Leu allele and to study the possible variations in Finland four DNA pools from different geographical areas of Finland were genotyped. No significant differences in the allele frequencies were observed (21-28%) except in the Eastern Kainuu area (13%), an area with an increased risk of mortality from coronary artery disease (CAD), supporting the results presented above. The association of FXIII 34Leu variant with a lower incidence of myocardial infarction suggests a new role for FXIII in a polygenic thrombotic disease.

Alleles↗