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L Peltonen

Publications and source records attributed to L Peltonen.

At least 19 recordsLinked to original sources
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

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↗
PubMed1999

Recurrence of Marfan syndrome as a result of parental germ-line mosaicism for an FBN1 mutation.

Mutations in the FBN1 gene cause Marfan syndrome (MFS), a dominantly inherited connective tissue disease. Almost all the identified FBN1mutations have been family specific, and the rate of new mutations is high. We report here a de novo FBN1mutation that was identified in two sisters with MFS born to clinically unaffected parents. The paternity and maternity were unequivocally confirmed by genotyping. Although one of the parents had to be an obligatory carrier for the mutation, we could not detect the mutation in the leukocyte DNA of either parent. To identify which parent was a mosaic for the mutation we analyzed several tissues from both parents, with a quantitative and sensitive solid-phase minisequencing method. The mutation was not, however, detectable in any of the analyzed tissues. Although the mutation could not be identified in a sperm sample from the father or in samples of multiple tissue from the mother, we concluded that the mother was the likely mosaic parent and that the mutation must have occurred during the early development of her germ-line cells. Mosaicism confined to germ-line cells has rarely been reported, and this report of mosaicism for the FBN1 mutation in MFS represents an important case, in light of the evaluation of the recurrence risk in genetic counseling of families with MFS.

Adult↗
PubMed1999

Genomewide scan for familial combined hyperlipidemia genes in finnish families, suggesting multiple susceptibility loci influencing triglyceride, cholesterol, and apolipoprotein B levels.

Familial combined hyperlipidemia (FCHL) is a common dyslipidemia predisposing to premature coronary heart disease (CHD). The disease is characterized by increased levels of serum total cholesterol (TC), triglycerides (TGs), or both. We recently localized the first locus for FCHL, on chromosome 1q21-q23. In the present study, a genomewide screen for additional FCHL loci was performed. In stage 1, we genotyped 368 polymorphic markers in 35 carefully characterized Finnish FCHL families. We identified six chromosomal regions with markers showing LOD score (Z) values >1.0, by using a dominant mode of inheritance for the FCHL trait. In addition, two more regions emerged showing Z>2.0 with a TG trait. In stage 2, we genotyped 26 more markers and seven additional FCHL families for these interesting regions. Two chromosomal regions revealed Z>2.0 in the linkage analysis: 10p11.2, Z=3.20 (theta=.00), with the TG trait; and 21q21, Z=2.24 (theta=.10), with the apoB trait. Furthermore, two more chromosomal regions produced Z>2.0 in the affected-sib-pair analysis: 10q11.2-10qter produced Z=2.59 with the TC trait and Z=2.29 with FCHL, and 2q31 produced Z=2.25 with the TG trait. Our results suggest additional putative loci influencing FCHL in Finnish families, some potentially affecting TG levels and some potentially affecting TC or apoB levels.

Adult↗
PubMed1999

Localization of the APECED protein in distinct nuclear structures.

Autoimmune-polyendocrinopathy-candidiasis-ecto-dermaldystrophy (APECED) is the only systemic autoimmune disease with a monogenic background known so far revealing no association with the major histocompatibility complex region. We have recently isolated the gene defective in this syndrome and characterized several different mutations in individuals with the disorder. The novel gene, AIRE, contains a putative bipartite nuclear targeting signal predicting a nuclear location of the corresponding protein. The presence of two PHD-type zinc finger domains as well as the newly described putative DNA-binding domain, SAND, in the amino acid sequence of the APECED protein implies that it may be involved in the regulation of gene expression. Using transient expression of AIRE cDNA in mammalian cells we demonstrate here the nuclear location of the APECED protein. Immunohistochemical staining of transfected cells revealed that most of the recombinant 58 kDa APECED protein is present in the form of nuclear dots. By double immuno-fluorescence labelling we further show that these APECED-containing structures and the previously described PML nuclear bodies are largely non-overlapping. The AIRE protein was also visualized in multiple human tissues: a subset of the cells in thymus, in spleen and in lymph node showed nuclear staining with APECED antiserum. Immunofluorescence labelling of peripheral blood mononuclear leukocytes also revealed a nuclear body-like staining pattern in a fraction of these cells. These data from both in vitro and ex vivo systems, together with the predicted structural features of the APECED protein, suggest that this protein is most probably involved in the regulation of gene expression.

Animals↗
PubMed1999

Novel genes for familial combined hyperlipidemia.

Familial combined hyperlipidemia (FCHL) is a complex genetic disorder of unknown etiology. Recently, 'modifier' genes of the FCHL phenotype, such as the apolipoprotein AI-CIII-AIV gene cluster and LPL, have been identified in several populations. A 'major' gene for FCHL has been identified in a Finnish isolate which maps to a region syntenic to murine chromosome 3 where a locus for combined hyperlipidemia has been identified. We review these and other recent studies which indicate that FCHL is genetically heterogeneous.

Age Factors↗
PubMed1999

Evidence for involvement of the type 1 angiotensin II receptor locus in essential hypertension.

Components of the renin-angiotensin system play an important role in the normal regulation of blood pressure. We carried out a comprehensive genetic linkage study of the genes involved in the renin-angiotensin cascade in Finnish hypertensive twins and their affected siblings. We found no evidence for linkage between essential hypertension and the genes coding for renin, angiotensinogen, angiotensin-converting enzyme, or kallikrein 1 in the 329 hypertensive individuals of 142 families studied. In contrast, two intragenic markers for the type 1 angiotensin II receptor (AT1) showed some evidence for linkage in the total sample. A closer examination of this gene locus was carried out using subgroups of nonobese sibpairs with early onset of hypertension and uniform geographical origin. These stratifications yielded suggestive evidence for linkage of hypertension to the genetic area containing the AT1 gene, with a maximal multipoint logarithm of the odds (LOD) score of 2.9. A genetic association study carried out in an independent series of 50 hypertensive cases and 122 normotensive controls showed an increase in the frequency of the A1166-->C allele of the AT1 gene in the hypertensive individuals. In a novel variant of model-free multipoint linkage analysis allowing linkage disequilibrium in the calculations, an LOD score of 5.13 was obtained. Sequence analyses of the entire coding region and 848 bp of promoter region in the DNA sample on 8 index samples did not reveal previously unpublished sequence variations. The data provide evidence that a common genetic variant of the AT1 gene locus influences the risk of essential hypertension in the Finnish population.

Adult↗
PubMed1999

High-resolution physical and genetic mapping of the critical region for Meckel syndrome and Mulibrey Nanism on chromosome 17q22-q23.

Previously, we assigned the genes for two autosomal recessive disorders, Meckel syndrome (MKS; MIM 249000) and Mulibrey Nanism [MUL (muscle-liver-brain-eye Nanism); MIM 253250] that are enriched in the Finnish population, to overlapping genomic regions on chromosome 17q. Now, we report the construction of a bacterial clone contig over the critical region for both disorders. Several novel CA-repeat markers were isolated from these clones, which allowed refined mapping of the MKS and MUL loci using haplotype and linkage disequilibrium analysis. The localization of the MKS locus was narrowed to <1 cM between markers D17S1290 and 132-CA, within an approximately 800-kb region. The MUL locus was refined into an approximately 1400-kb interval between markers D17S1290 and 52-CA. The whole MKS region falls within the MUL region. In the common critical region, the conserved haplotypes were different in MKS and MUL patients. A trancript map was constructed by assigning expressed sequence tags (ESTs) and genes, derived from the human gene map, to the bacterial clone contig. Altogether, four genes and a total of 20 ESTs were precisely localized. These data provide the molecular tools for the final identification of the MKS and the MUL genes.

Chromosome Mapping↗
PubMed1999

Mapping ESTs by fiber-FISH.

A visual transcript map of six genes was constructed on the chromosome 21q22.3 by high resolution fluorescence in situ hybridization (FISH). Expressed sequence tags (ESTs) from six genes-PWP2, KNP1, AIRE, C21orf3, SMT3A, and C21orf1-were successfully localized by fiber-FISH by use of sensitive tyramide-based detection. The sizes of the ESTs varied between 315 to 956 bp and most of them map within the 3'-untranslated region. The ESTs were assigned to and subsequently ordered within cosmid, PAC, and BAC clones hybridized on DNA fibers. Physical distances between ESTs and known markers were determined. Our results demonstrate the feasibility and accuracy of visual mapping EST sequences in relation to known markers. The main advantage of this approach is that it can be applied to finely map any of the database ESTs for positional cloning efforts. The sensitivity, specificity, and reproducibility of this high-resolution EST mapping technique is evaluated.

3' Untranslated Regions↗
PubMed1998

Fine-scale mapping of a novel dementia gene, PLOSL, by linkage disequilibrium.

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL; MIM 221770) is a rare hereditary cause of presenile dementia with autosomal recessive inheritance. Its unique feature is the cystic bone lesions that accompany the dementia. About 160 cases have been reported to date, mostly in Finland and Japan. The etiology and pathogenesis of PLOSL are unknown. We recently assigned the locus for PLOSL in the Finnish population to chromosome 19q13.1 (P. Pekkarinen et al., 1998, Am. J. Hum. Genet. 62, 362-272). In the present study, we restrict the critical region for PLOSL to 153 kb by linkage-disequilibrium mapping. First, three new microsatellite markers were revealed in the PLOSL critical region. These and three other markers spanning the critical region were analyzed in Finnish PLOSL families. Strong linkage disequilibrium (multipoint P value < 10(-47)) was detected between the markers and PLOSL, and for two markers, D19S1176 and D19S610, all the PLOSL chromosomes shared identical 171- and 218-bp alleles, respectively. Haplotype analysis revealed five different haplotypes in the Finnish PLOSL chromosomes. But all of them shared the region between markers D19S1175 and D19S608 that could be traced to one ancestor haplotype by single recombination events, thus defining the critical region as 153 kb. Multipoint association analysis also assigned the most likely location of the PLOSL locus within this interval to the immediate vicinity of marker D19S610. A promising positional candidate for PLOSL, an amyloid precursor-like protein, was studied by sequencing, but no mutations were detected. These results lay the basis for the cloning of this novel dementia gene and for diagnostics in the Finnish population using haplotype analysis.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Intragenic polymorphisms of the vitamin D receptor gene associated with intervertebral disc degeneration.

STUDY DESIGN: A study in genetic epidemiology of disc degeneration, based on lifetime exposure data, findings on magnetic resonance imaging, and genotyping of intragenic markers. OBJECTIVES: To pursue the potential correlation between common allelic variations in the vitamin D receptor locus and degeneration of the intervertebral disc. SUMMARY OF BACKGROUND DATA: Familial aggregation has been observed in intervertebral disc degeneration, but the relative significance of the genetic component and shared environmental influences is unknown. The identification of relevant candidate genes associated with disc degeneration would specify a genetic component and increase our understanding of the etiopathogenesis of disc degeneration. METHODS: From the population-based Finnish Twin cohort, 85 pairs of male monozygotic twins were selected based on exposure to suspected risk factors for disc degeneration. Interview data were gathered on relevant lifetime exposures, and thoracic and lumbar disc degeneration was determined through quantitative and qualitative assessments of signal intensity on magnetic resonance imaging, and qualitative assessments of disc bulging and disc height narrowing. Possible associations were examined between disc degeneration measures and two polymorphisms of the coding region of the vitamin D receptor locus. RESULTS: Two intragenic polymorphisms of the vitamin D receptor gene revealed an association with disc degeneration. Quantitatively assessed signal intensities of thoracic and lumbar (T6-S1) discs were 12.9% worse in men with the Taql tt genotype and 4.5% worse in men with the Tt genotype, compared with signal intensity in men with the TT genotype (age adjusted P = 0.003). A similar pattern was found between disc signal intensity and Fokl genotypes; men with the ff and Ff genotypes had mean signal intensities that were 9.3% and 4.3% lower, respectively, than those in men with FF genotypes (age-adjusted P = 0.006). The summary scores of qualitatively assessed signal intensity, bulging, and disc height were 4.0% and 6.9% worse in men with Ff and ff genotypes, respectively, when compared with those in men with the FF genotype (age-adjusted P = 0.029). CONCLUSION: Specific vitamin D receptor alleles were associated with intervertebral disc degeneration as measured by T2-weighted signal intensity, demonstrating for the first time, the existence of genetic susceptibility to this progressive, age-related degenerative process.

Adult↗
PubMed1998

Expression and endocytosis of lysosomal aspartylglucosaminidase in mouse primary neurons.

Aspartylglucosaminuria (AGU) is a neurodegenerative lysosomal storage disease that is caused by mutations in the gene encoding for a soluble hydrolase, aspartylglucosaminidase (AGA). In this study, we have used our recently developed mouse model for AGU and analyzed processing, intracellular localization, and endocytosis of recombinant AGA in telencephalic AGU mouse neurons in vitro. The processing steps of AGA were found to be similar to the peripheral cells, but both the accumulation of the inactive precursor molecule and delayed lysosomal processing of the enzyme were detected. AGA was distributed to the cell soma and neuronal processes but was not found in the nerve terminals. Endocytotic capability of cultured telencephalic neurons was comparable to that of fibroblasts, and endocytosis of AGA was blocked by free mannose-6-phosphate (M6P), indicating that uptake of the enzyme was mediated by M6P receptors (M6PRs). Uptake of extracellular AGA was also studied in the tumor-derived cell lines rat pheochromocytoma (PC12) and mouse neuroblastoma cells (N18), which both endocytosed AGA poorly as compared with cultured primary neurons. Expression of cation-independent M6PRs (CI-M6PRs) in different cell lines correlated well with the endocytotic capability of these cells. Although a punctate expression pattern of CI-M6PRs was found in fibroblasts and cultured primary neurons, the expression was beyond the detection limit in PC12 and N18 cells. This indicates that PC12 and N18 are not feasible cell lines to describe neuronal uptake of mannose-6-phosphate-tagged proteins. This in vitro data will form an important basis for the brain-targeted therapy of AGU.

Animals↗
PubMed1998

Activation and oligomerization of aspartylglucosaminidase.

Secretory, membrane, and lysosomal proteins undergo covalent modifications and acquire their secondary and tertiary structure in the lumen of the endoplasmic reticulum (ER). In order to pass the ER quality control system and become transported to their final destinations, many of them are also assembled into oligomers. We have recently determined the three-dimensional structure of lysosomal aspartylglucosaminidase (AGA), which belongs to a newly discovered family of homologous amidohydrolases, the N-terminal nucleophile hydrolases. Members of this protein family are activated from an inactive precursor molecule by an autocatalytic proteolytic processing event whose exact mechanism has not been thoroughly determined. Here we have characterized in more detail the initial events in the ER required for the formation of active AGA enzyme using transient expression of polypeptides carrying targeted amino acid substitutions. We show that His124 at an interface between two heterodimers of AGA is crucial for the thermodynamically stable oligomeric structure of AGA. Furthermore, the side chain of Thr206 is essential both for the proteolytic activation and enzymatic activity of AGA. Finally, the proper geometry of the residues His204-Asp205 seems to be crucial for the activation of AGA precursor polypeptides. We propose here a reaction mechanism for the activation of AGA which could be valid for homologous enzymes as well.

Amino Acid Sequence↗
PubMed1998

Cells of the neuronal lineage play a major role in the generation of amyloid precursor fragments in gelsolin-related amyloidosis.

Gelsolin-related amyloidosis or familial amyloidosis, Finnish type (FAF) (OMIM No105120) is a hereditary amyloid disease caused by a mutation in a precursor protein for amyloid (gelsolin) and characterized by corneal dystrophy and polyneuropathy. In vitro expression of the FAF-mutant (Asp187 --> Asn/Tyr) secretory gelsolin in COS cells leads to generation of an aberrant polypeptide presumably representing the precursor for tissue amyloid. Here, we provide evidence that this abnormal processing results from defective initial folding of the secreted FAF gelsolin due to the lack of the Cys188-Cys201 disulfide bond, normally formed next to the FAF mutation site. We compared cells of different tissue origin and discovered a dramatic difference between the amount of cleavage of FAF gelsolin to the amyloid precursor in neuronal and non-neuronal cells. More than half of the mutant gelsolin was cleaved in PC12 and in vitro differentiated human neuronal progenitor cells. In contrast, human fibroblasts and Schwannoma cell cultures showed only a limited capacity to cleave FAF gelsolin, although the cleavage mechanism per se seems to be similar in the various cell types. The present findings of processing and distribution of secreted FAF gelsolin in the neuronal cells emphasize the role of neurons in the tissue pathogenesis of this amyloid polyneuropathy.

Amyloid Neuropathies↗
PubMed1998

Cloning of a novel human putative type Ia integral membrane protein mapping to 21q22.3.

The distal part of human chromosome 21q22.3 is exceptionally gene rich and contains several loci that have been linked to hereditary disorders. In the course of constructing an extensive transcript map for chromosome 21, we have isolated numerous coding segments in 21q22.3 that represent potential candidate genes in this region. Following this approach, we have cloned a novel single-copy gene (C21orf3) (HGMW-approved symbol C21orf1) expressed as a unique 2.69-kb mRNA in a wide range of tissues. We have precisely mapped C21orf3 by fiber FISH distal to marker D21S171. The C21orf3 gene encodes a predicted protein of 180 residues that does not share any sequence homology with other known proteins. C21orf3 harbors predicted structural features of a type Ia integral membrane protein and contains a tetrapeptide motif (YXRF) observed in several cell surface proteins involved in signal transduction. Although the function of C21orf3 is still unknown, this novel gene may play an important role in a cell trafficking mechanism.

Amino Acid Sequence↗
PubMed1998

Marfan Database (third edition): new mutations and new routines for the software.

The Marfan database is a software that contains routines for the analysis of mutations identified in the FBN1 gene that encodes fibrillin-1. Mutations in this gene are associated not only with Marfan syndrome but also with a spectrum of overlapping disorders. The third version of the Marfan database contains 137 entries. The software has been modified to accommodate four new routines and is now accessible on the World Wide Web at http://www.umd.necker.fr

Computer Communication Networks↗