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Now showing items 1 - 16 of 20

  • Confirmation of the type 2 myotonic dystrophy (CCTG)(n) expansion mutation in patients with proximal myotonic myopathy/proximal myotonic dystrophy of different European origins: A single shared haplotype indicates an ancestral founder effect RID A-9210-2012

    Bachinski, LL   Udd, B   Meola, G   Sansone, V   Bassez, G   Eymard, B   Thornton, CA   Moxley, RT   Harper, PS   Rogers, MT   Jurkat-Rott, K   Lehmann-Horn, F   Wieser, T   Gamez, J   Navarro, C   Bottani, A   Kohler, A   Shriver, MD   Sallinen, R   Wessman, M   Zhang, SX   Wright, FA   Krahe, R  

    Myotonic dystrophy (DM), the most common form of muscular dystrophy in adults, is a clinically and genetically heterogeneous neuromuscular disorder. DM is characterized by autosomal dominant inheritance, muscular dystrophy, myotonia, and multisystem involvement. Type 1 DM (DM1) is caused by a (CTG)(n) expansion in the 3' untranslated region of DMPK in 19q13.3. Multiple families, predominantly of German descent and with clinically variable presentation that included proximal myotonic myopathy (PROMM) and type 2 DM (DM2) but without the DM1 mutation, showed linkage to the 3q21 region and were recently shown to segregate a (CCTG)(n) expansion mutation in intron 1 of ZNF9. Here, we present linkage to 3q21 and mutational confirmation in 17 kindreds of European origin with PROMM and proximal myotonic dystrophy, from geographically distinct populations. All patients have the DM2 (CCTG)(n) expansion. To study the evolution of this mutation, we constructed a comprehensive physical map of the DM2 region around ZNF9. High-resolution haplotype analysis of disease chromosomes with five microsatellite and 22 single-nucleotide polymorphism markers around the DM2 mutation identified extensive linkage disequilibrium and a single shared haplotype of at least 132 kb among patients from the different populations. With the exception of the (CCTG)(n) expansion, the available markers indicate that the DM2 haplotype is identical to the most common haplotype in normal individuals. This situation is reminiscent of that seen in DM1. Taken together, these data suggest a single founding mutation in DM2 patients of European origin. We estimate the age of the founding haplotype and of the DM2 (CCTG) expansion mutation to be similar to200-540 generations.
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  • Clinical characteristics of migraine in a population-based twin sample: similarities and differences between migraine with and without aura RID A-1820-2008

    Kallela, M   Wessman, M   Farkkila, M   Palotie, A   Koskenvuo, M   Honkasalo, ML   Kaprio, J  

    Objective: To look into clinical differences between migraine with and without aura in a population-based sample of migraineurs. Background: Migraine presents in two major forms, migraine with and migraine without aura. With the exception of the aura phase, the clinical characteristics of these entities are very similar. Despite this, however, the recent epidemiological data underline differences between migraine with and without aura. We tried to examine whether other features besides the aura differ between these two major forms of migraine. Methods: We studied 321 twins suffering from migraine with aura and 166 twins with migraine without aura from the population-based Finnish Twin Cohort. Migraine was diagnosed according to the criteria of the international Headache Society (MS). Analysis was based on the combination of a mailed questionnaire and a telephone interview by a neurologist. Special attention was paid to differences between migraine with and without aura. results: Some qualities of headaches differed between MS defined migraine with and without aura. Unilateral headache (Chi-squared p=0.039) and photophobia (Chi-squared p=0.010) were more typical for migraine with aura, while nausea was more typical for migraine without aura (Chi-squared p = 0.002). Duration of headache in migraine without aura was also longer than in migraine with aura (Mann-Whitney U-test 0.007). Conclusions: There are clinical differences between MS defined migraine with and without aura; even the headache phase between the two entities differs. It is worthwhile distinguishing between them when looking for the elusive genes for these more common forms of migraine.
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  • Association analysis of the AIRE and insulin genes in Finnish type 1 diabetic patients

    Turunen, JA   Wessman, M   Forsblom, C   Kilpikari, R   Parkkonen, M   Pontynen, N   Ilmarinen, T   Ulmanen, I   Peltonen, L   Groop, PH  

    Mutations in the autoimmune regulator (AIRE) gene cause a recessive Mendelian disorder autoimmune polyendocrinopathy syndrome type 1 (APS-1 or autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy). APS-1 patients develop multiorgan autoimmune diseases including type 1 diabetes (prevalence 12%). The AIRE protein controls the central tolerance induction in the thymus by regulating the expression levels of tissue-specific peripheral antigens, such as insulin. We hypothesized that the insulin gene (INS) polymorphisms together with the AIRE variations may predispose individuals to diabetes. The role of the AIRE gene was tested both independently and on the condition of the INS risk genotype in the Finnish type 1 diabetes sample. A total of 733 type 1 diabetic cases and 735 age- and sex-matched healthy controls were used in the analysis. Five common single nucleotide polymorphisms (SNPs) in the AIRE gene were selected from the public database (dbSNP). The -23HphI polymorphism was used as a surrogate marker for the INS gene promoter repeat. The five genotyped SNPs in the AIRE gene showed no evidence of association with type 1 diabetes. As expected, the INS gene polymorphism -23HphI was significantly associated with susceptibility to type 1 diabetes (P=6.8x10(-12), chi(2) test). When the subclass of patients carrying the homozygote genotype of the INS gene was used in the analysis, the AIRE polymorphisms showed no association with the disease. In conclusion, the AIRE gene does not seem to contribute to disease susceptibility in Finnish type 1 diabetic patients, whereas the insulin gene represents a notable risk factor for disease in this population.
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    Fetal male cells from maternal venous blood were detected by a non-radioactive in situ hybridization method using the biotinylated Y-specific DNA probe pY431. The hybridizations were performed on Ficoll-Paque-isolated nucleated blood cells obtained from 11 pregnant women in the seventh to 31st week of gestation. A Y-specific signal was detected in both granulocytes and lymphocyte-like cells in seven of the 11 women studied. These women gave birth to boys. In one of the four remaining cases, a Y-specific signal was detected in the lymphocyte-like cells but not in the granulocytes. This woman gave birth to a girl. The other three women had no cells with a Y-specific signal and all three gave birth to girls. Altogether, 83 500 nucleated cells were analysed. One hundred and three cells showed a Y-specific signal. Of these Y-specific cells, 62 per cent were granulocytes and 38 per cent lymphocyte-like cells. Our results suggest that fetomaternal transfer of granulocytes is common and that it occurs as early as in the seventh week of gestation. None of the ten non-pregnant female control samples showed positive cells with the Y-chromosome-specific probe; approximately 97 per cent of the cells from the five adult male controls showed a Y-specific signal. Our results indicate that in situ hybridization using a Y-specific DNA probe performed on granulocytes in maternal blood can be used for fetal male sex determination.
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  • A quality assessment survey of SNP genotyping laboratories RID A-9179-2008

    Lahermo, P   Liljedahl, U   Alnaes, G   Axelsson, T   Brookes, AJ   Ellonen, P   Groop, PH   Hallden, C   Holmberg, D   Holmberg, K   Keinanen, M   Kepp, K   Kere, J   Kiviluoma, P   Kristensen, V   Lindgren, C   Odeberg, J   Osterman, P   Parkkonen, M   Saarela, J   Sterner, M   Stromqvist, L   Talas, U   Wessman, M   Palotie, A   Syvanen, AC  

    To survey the quality of SNP genotyping, a joint Nordic quality assessment (QA) round was organized between 11 laboratories in the Nordic and Baltic countries. The QA round involved blinded genotyping of 47 DNA samples for 18 or six randomly selected SNPs. The methods used by the participating laboratories included all major platforms for small, to medium-size SNP genotyping. The laboratories used their standard procedures for SNP assay design, genotyping, and quality control. Based on the joint results from all laboratories, a consensus genotype for each DNA sample and SNP was determined by the coordinator of the survey, and the results from each laboratory were compared to this genotype. The overall genotyping accuracy achieved in the survey was excellent. Six laboratories delivered genotype data that were in full agreement with the consensus genotype. The average accuracy per SNP varied from 99.1 to 100% between the laboratories, and it was frequently 100% for the majority of the assays for which SNP genotypes were reported. Lessons from the survey are that special attention should be given to the quality of the DNA samples prior to genotyping, and that a conservative approach for calling the genotypes should be used to achieve a high accuracy. Hum Mutat 27(7), 711-714,2006. (c) 2006 Wiley-Liss, Inc.
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  • Novel splice site CACNA1A mutation causing episodic ataxia type 2.

    Kaunisto, M A   Harno, H   Kallela, M   Somer, H   Sallinen, R   Hamalainen, E   Miettinen, P J   Vesa, J   Orpana, A   Palotie, A   Farkkila, M   Wessman, M  

    Episodic ataxia type 2 (EA-2) is an autosomal dominant neurological disorder, characterized by episodes of ataxia, vertigo, nausea, nystagmus, and fatigue, associated with acetazolamide responsiveness. The disease is caused by mutations in the P/Q-type calcium channel Ca(v)2.1 subunit gene, CACNA1A, located on chromosome 19p13.2. We analyzed a family with 13 affected individuals for linkage to this locus and reached a two-point maximum LOD score of 4.48. A novel CACNA1A mutation, IVS36-2A>G, at the 3' acceptor splice site of intron 36 was identified by sequencing. It is the first described CACNA1A acceptor splice site mutation and the most C-terminal EA-2-causing mutation reported to date.
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  • Chromosome 19p13 loci in Finnish migraine with aura families RID A-1820-2008

    Kaunisto, MA   Tikka, PJ   Kallela, M   Leal, SM   Papp, JC   Korhonen, A   Hamalainen, E   Harno, H   Havanka, H   Nissila, M   Sako, E   Ilmavirta, M   Kaprio, J   Farkkila, M   Ophoff, RA   Palotie, A   Wessman, M  

    Chromosomal area 19p13 contains two migraine associated genes: a Ca(v)2.1 (P/Q-type) calcium channel alpha(1) subunit gene, CACNA1A, and an insulin receptor gene, INSR. Missense mutations in CACNA1A cause a rare Mendelian form of migraine, familial hemiplegic migraine type 1 (FHM1). Contribution of CACNA1A locus has also been studied in the common forms of migraine, migraine with (MA) and without aura (MO), but the results have been contradictory. The role of INSR is less well established: A region on 19p13 separate from CACNA1A was recently reported to be a major locus for migraine and subsequently, the INSR gene was associated with MA and MO. Our aim was to clarify the role of these loci in MA families by analyzing 72 multigenerational Finnish MA families, the largest family sample so far. We hypothesized that the potential major contribution of the 19p13 loci should be detected in a family sample of this size, and this was confirmed by simulations. We genotyped eight polymorphic microsatellite markers surrounding the INSR and CACNA1A genes on 757 individuals. Using parametric and non-parametric linkage analysis, none of the studied markers showed any evidence of linkage to MA either under locus homogeneity or heterogeneity. However, marginally positive lod scores were observed in three families, and thus for these families the results remain inconclusive. The overall conclusion is that our study did not provide evidence of a major MA susceptibility region on 19p13 and thus we were not able to replicate the INSR locus finding. This article contains supplementary material, which may be viewed at the American Journal of Medical Genetics website at http:// (C) 2004 Wiley-Liss, Inc.
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  • Trait components provide tools to dissect the genetic susceptibility of migraine RID A-1820-2008

    Anttila, V   Kallela, M   Oswell, G   Kaunisto, MA   Nyholt, DR   Hamalainen, E   Havanka, H   Ilmavirta, M   Terwilliger, J   Sobel, E   Peltonen, L   Kaprio, J   Farkkila, M   Wessman, M   Palotie, A  

    The commonly used "end diagnosis" phenotype that is adopted in linkage and association studies of complex traits is likely to represent an oversimplified model of the genetic background of a disease. This is also likely to be the case for common types of migraine, for which no convincingly associated genetic variants have been reported. In headache disorders, most genetic studies have used end diagnoses of the International Headache Society ( IHS) classification as phenotypes. Here, we introduce an alternative strategy; we use trait components-individual clinical symptoms of migraine-to determine affection status in genomewide linkage analyses of migraine-affected families. We identified linkage between several traits and markers on chromosome 4q24 ( highest LOD score under locus heterogeneity [ HLOD] 4.52), a locus we previously reported to be linked to the end diagnosis migraine with aura. The pulsation trait identified a novel locus on 17p13 ( HLOD 4.65). Additionally, a trait combination phenotype ( IHS full criteria) revealed a locus on 18q12 ( HLOD 3.29), and the age at onset trait revealed a locus on 4q28 ( HLOD 2.99). Furthermore, suggestive or nearly suggestive evidence of linkage to four additional loci was observed with the traits phonophobia ( 10q22) and aggravation by physical exercise ( 12q21, 15q14, and Xp21), and, interestingly, these loci have been linked to migraine in previous studies. Our findings suggest that the use of symptom components of migraine instead of the end diagnosis provides a useful tool in stratifying the sample for genetic studies.
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  • Polymorphisms in the gene encoding angiotensin I converting enzyme 2 and diabetic nephropathy.

    Frojdo, S   Sjolind, L   Parkkonen, M   Makinen, V-P   Kilpikari, R   Pettersson-Fernholm, K   Forsblom, C   Fagerudd, J   Tikellis, C   Cooper, M E   Wessman, M   Groop, P-H  

    AIMS/HYPOTHESIS: Substantial evidence exists for the involvement of the renin-angiotensin system (RAS) in diabetic nephropathy. Angiotensin I converting enzyme 2 (ACE2), a new component of the RAS, has been implicated in kidney disease, hypertension and cardiac function. Based on this, the aim of the present study was to evaluate whether variations in ACE2 are associated with diabetic nephropathy.MATERIALS AND METHODS: We used a cross-sectional, case-control study design to investigate 823 Finnish type 1 diabetic patients (365 with and 458 without nephropathy). Five single-nucleotide polymorphisms (SNPs) were genotyped using TaqMan technology. Haplotypes were estimated using PHASE software, and haplotype frequency differences were analysed using a chi(2)-test-based tool.RESULTS: None of the ACE2 polymorphisms was associated with diabetic nephropathy, and this finding was supported by the haplotype analysis. The ACE2 polymorphisms were not associated with blood pressure, BMI or HbA(1)c.CONCLUSIONS/INTERPRETATION: In Finnish type 1 diabetic patients, ACE2 polymorphisms are not associated with diabetic nephropathy or any studied risk factor for this complication. Further studies are necessary to assess a minor effect of ACE2.
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  • Analysis of genotype and phenotype on the same interphase or mitotic cell. A manual of MAC (morphology antibody chromosomes) methodology.

    Knuutila, S   Nylund, S J   Wessman, M   Larramendy, M L  

    The purpose of this paper is to serve as a MAC (Morphology Antibody Chromosome) manual describing combined methodologies that allow simultaneous and/or sequential analysis of cell morphology, immunophenotype, and banded chromosomes and/or in situ hybridization signals. The MAC techniques used at the Department of Medical Genetics of the University of Helsinki, Finland, are described and modifications or related techniques reported by other authors are discussed. A list of references concerning applications is also given.
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  • A novel missense ATP1A2 mutation in a Finnish family with familial hemiplegic migraine type 2

    Kaunisto, MA   Harno, H   Vanmolkot, KRJ   Gargus, JJ   Sun, G   Hamalainen, E   Liukkonen, E   Kallela, M   van den Maagdenberg, AMJM   Frants, RR   Farkkila, M   Palotie, A   Wessman, M  

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  • Chromosomal localization of SLC12A5/Slc72a5, the human and mouse genes for the neuron-specific K+-Cl- cotransporter (KCC2) defines a new region of conserved homology

    Sallinen, R   Tornberg, J   Putkiranta, M   Horelli-Kuitunen, N   Airaksinen, MS   Wessman, M  

    K+-Cl- cotransporters (KCCs) constitute a branch of the cation-chloride cotransporter (CCC) family. To date, four KCC isoforms (KCC1-KCC4) have been identified and they all mediate obligatorily coupled, electroneutral transmembrane movement of K+ and Cl- ions. KCC2 (gene symbol SLC12A5) is expressed exclusively in neurons within the central nervous system and abnormalities in its expression have been proposed to play a role in pathological conditions such as epilepsy and neuronal trauma. Here we have determined chromosome location of both the human and the mouse genes encoding KCC2, which may assist in future efforts to determine the contribution of KCC2 to inherited human disorders. We assigned human SLC12A5 to 20q12 --> q13.1 and its murine homolog, Slc12a5, to 5G2-G3 by fluorescence in situ hybridization (FISH). These mapping data are contradictory to the previously reported human-mouse conserved synteny relationships disrupting an exceptionally well-conserved homology segment between human Chr 20 and mouse Chr 2. We hence suggest the first region of conserved homology between human Chr 20 and mouse Chr 5. Copyright (C) 2001 S. Karger AG, Basel.
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  • Physical mapping of mouse collagen genes on Chromosome 10 by high-resolution FISH

    Sallinen, R   Latvanlehto, A   Kvist, AP   Rehn, M   Eerola, I   Chu, ML   Bonaldo, P   Saitta, B   Bressan, GM   Pihlajaniemi, T   Vuorio, E   Palotie, A   Wessman, M   Horelli-Kuitunen, N  

    Fluorescence in situ hybridization (FISH) on mechanically stretched chromosomes (MSCs) and extended DNA fibers enables construction of high-resolution physical maps by accurate ordering and orienting genomic clones as well as by measuring physical lengths of gaps and overlaps between them. These high-resolution FISH targets have hitherto been used mainly in the study of the human genome. Here we have applied both MSCs and extended DNA fibers to the physical mapping of the mouse genome. At first, five mouse collagen genes were localized by metaphase-FISH: Coll0a1 to chromosomal bands 10B1-B3; Coll3a1 to 10B4; and Col6a1, Col6a2, and Col18a1 to 10B5-C1. The mutual order of the genes, centromere-Col10a1-Col13a1-Col6a2-Col6a1-Col18a1-telomere, was determined by FISH on metaphase chromosomes, MSCs, and extended DNA fibers. To our knowledge, this is the first time mouse metaphase chromosomes have been stretched and used as targets for FISH. We also used MSCs to determine the transcriptional orientations, telomere-5 ' -3 ' -centromere, of both Col13a1 and Col18a1. With fiber-FISH, Col18a1, Col6a1, and Col6a2 were shown to be in a head-to-tail configuration with respective intergenic distances of about 350 kb and 90 kb. Comparison of our physical mapping results with the homologous human data reveals both similarities and differences concerning the chromosomal distribution, order, transcriptional orientations, and intergenic distances of the collagen genes studied.
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    Human immunodeficiency virus type 1 (HIV-1) infection was studied in two different human neuroblastoma cell lines, SK-N-MC and SH-SY5Y. Results from immunofluorescence analysis indicate that SK-N-MC cells express a 68K neurofilament, and SH-SY5Y cells express additionally a 160K to 200K neurofilament complex and thus represent a more differentiated state. HIV-1 infection in these cell lines was demonstrated by nested polymerase chain reaction and further characterized by in situ hybridization, which showed that about 50 % of SK-N-MC cells and 20 % of SH-SY5Y cells were infected by HIV-1 and contained integrated proviral HIV-1 DNA. Among the cytokines and growth factors studied, tumour necrosis factor alpha (TNF-alpha) enhanced virus production in both cell lines, but to a differing extent, according to our mRNA and p24 antigen capture assay. In SK-N-MC cells the enhancement of HIV- 1 mRNA was detected after 24 h of stimulation, and declined to the control level by 48 h. In SH-SY5Y cells a clear-cut stimulation was seen at both time points. By contrast, interleukin-6 (IL-6) enhanced the virus replication only in SK-N-MC cells, as shown at the mRNA level. Immunochemical staining showed no differences in the proportion of HIV-1-positive cells after 48 h of stimulation by TNF-alpha or IL-6 when compared to the control cells. In addition, based on a thymidine incorporation assay, TNF-alpha inhibited, but IL-6 strongly increased, the DNA synthesis in SK-N-MC cells, whereas in the SH-SY5Y cell line no such differences were seen. We discuss the possibility that developing, less-differentiated neurons may be more readily infected by HIV-1 than fully differentiated neurons, and that cytokines such as TNF-alpha and IL-6, which are elevated in HIV-1-infected individuals, may enhance HIV production.
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