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Now showing items 1 - 5 of 5

  • 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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  • 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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  • 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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  • New methods for molecular diagnosis and demonstration of the (CCTG)n mutation in myotonic dystrophy type 2 (DM2)

    Sallinen, R   Vihola, A   Bachinski, LL   Huoponen, K   Haapasalo, H   Hackman, P   Zhang, S   Sirito, M   Kalimo, H   Meola, G   Horelli-Kuitunen, N   Wessman, M   Krahe, R   Udd, B  

    Myotonic dystrophy types 1 and 2 are autosomal dominant, multisystemic disorders with many similarities in their clinical manifestations. Myotonic dystrophy type 1 is caused by a (CTG)n expansion in the 3' untranslated region of the DMPK gene in 19q13.3 and myotonic dystrophy type 2 by a (CCTG)n expansion in intron 1 of ZNF9 in 3q21.3. However, the clinical diagnosis of myotonic dystrophy type 2 is more complex than that of myotonic dystrophy type 1, and conventional molecular genetic methods used for diagnosing myotonic dystrophy type 1 are insufficient for myotonic dystrophy type 2. Herein we describe two in situ hybridization protocols for the myotonic dystrophy type 2 mutation detection. Chromogenic in situ hybridization was used to detect both the genomic expansion and the mutant transcripts in muscle biopsy sections. Chromogenic in situ hybridization can be used in routine myotonic dystrophy type 2 diagnostics. Fluorescence in situ hybridization on extended DNA fibers was used to directly visualize the myotonic dystrophy type 2 mutation and to estimate the repeat expansion sizes. (C) 2004 Elsevier B.V. All rights reserved.
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