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Now showing items 1 - 10 of 10

  • A signal, from human mtDNA, of postglacial recolonization in Europe

    Torroni, A   Bandelt, HJ   Macaulay, V   Richards, M   Cruciani, F   Rengo, C   Martinez-Cabrera, V   Villems, R   Kivisild, T   Metspalu, E   Parik, JR   Tolk, HV   Tambets, K   Forster, P   Karger, B   Francalacci, P   Rudan, P   Janicijevic, B   Rickards, O   Savontaus, ML   Huoponen, K   Laitinen, V   Koivumaki, S   Sykes, B   Hickey, E   Novelletto, A   Moral, P   Sellitto, D   Coppa, A   Al-Zaheri, N   Santachiara-Benerecetti, AS   Semino, O   Scozzari, R  

    Mitochondrial HVS-I sequences from 10,365 subjects belonging to 56 populations/geographical regions of western Eurasia and northern Africa were first surveyed for the presence of the T -->C transition at nucleotide position 16298, a mutation which has previously been shown to characterize haplogroup V mtDNAs. All mtDNAs with this mutation were then screened for a number of diagnostic RFLP sites, revealing two major subsets of mtDNAs. One is haplogroup V proper, and the other has been termed "pre* V," since it predates V phylogenetically. The rather uncommon pre* V tends to be scattered throughout Europe (and northwestern Africa), whereas V attains two peaks of frequency: one situated in southwestern Europe and one in the Saami of northern Scandinavia. Geographical distributions and ages support the scenario that pre* V originated in Europe before the Last Glacial Maximum (LGM), whereas the more recently derived haplogroup V arose in a southwestern European refugium soon after the LGM. The arrival of V in eastern/central Europe, however, occurred much later, possibly with (post-) Neolithic contacts. The distribution of haplogroup V mtDNAs in modern European populations would thus, at least in part, reflect the pattern of postglacial human recolonization from that refugium, affecting even the Saami. Overall, the present study shows that the dissection of mtDNA variation into small and well-defined evolutionary units is an essential step in the identification of spatial frequency patterns. Mass screening of a few markers identified using complete mtDNA sequences promises to be an efficient strategy for inferring features of human prehistory.
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  • Hazards associated with pregnancies and deliveries in lysinuric protein intolerance

    Tanner, L   Nanto-Salonen, K   Niinikoski, H   Erkkola, R   Huoponen, K   Simell, O  

    Lysinuric protein intolerance (LPI) is an autosomal recessive transport disorder of the dibasic amino acids. The defect leads to deficiency of lysine, arginine, and ornithine and, secondarily, to a functional disorder of the urea cycle. Transient postprandial hyperammonemia and subsequent persistent protein aversion, linked with several other biochemical and clinical characteristics of the disease, suggest an increased risk for maternal and fetal complications during pregnancy and delivery. Our unique material on the outcomes of 18 pregnancies of 9 Finnish mothers with LPI and the follow-up of their 19 children shows that maternal LPI is truly associated with increased risk of anemia, toxemia, and intrauterine growth retardation during pregnancy and bleeding complications during delivery. Successful pregnancies and deliveries can still be achieved with careful follow-up of blood pressure and laboratory values. The children of the mothers with LPI generally develop normally. Special care of maternal protein nutrition and control of ammonemia, anemia, and toxemia during pregnancy are essential. We propose centralization of deliveries to obstetric units with capability to deal with bleeding complications and rare inborn errors of metabolism. (c) 2006 Elsevier Inc. All rights reserved.
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  • Segregation of the ND4/11778 and the ND1/3460 mutations in four heteroplasmic LHON families

    Puomila, A   Viitanen, T   Savontaus, ML   Nikoskelainen, E   Huoponen, K  

    Leber hereditary optic neuropathy (LHON) is an ocular disease associated with mutations in the mitochondrial DNA (mtDNA). The level of heteroplasmy in the mtDNA mutations ND4/11778 and ND1/3460 was followed over a period of 4-12 years in blood samples taken from nine members of four heteroplasmic LHON families. In addition, hair follicle and urinary tract epithelium samples of one individual were studied. The quantification of heteroplasmy was performed using the solid-phase minisequencing method. Only minor and random shifts in the heteroplasmy levels were observed over time, but there were no systematic changes towards an increasing or decreasing proportion of either LHON mutant in the individuals. This indicates that there is no selection for either mtDNA genotype but the segregation of the wildtype mtDNAs and those carrying LHON mutations is a stochastic process governed by random genetic drift. In this respect, LHON mutations seem to behave like neutral polymorphisms. (C) 2002 Elsevier Science B.V All rights reserved.
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  • mtDNA haplogroups and frequency patterns in Europe

    Torroni, A   Richards, M   Macaulay, V   Forster, P   Villems, R   Norby, S   Savontaus, ML   Huoponen, K   Scozzari, R   Bandelt, HJ  

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  • Leber's "plus": neurological abnormalities in patients with Leber's hereditary optic neuropathy.

    Nikoskelainen, E K   Marttila, R J   Huoponen, K   Juvonen, V   Lamminen, T   Sonninen, P   Savontaus, M L  

    Previous studies suggest that Leber's hereditary optic neuropathy (LHON) may be a systemic disorder with manifestations in organs other than the optic nerves. To evaluate nervous system involvement 38 men and eight women with LHON were re-examined. The patients were divided into three groups according to mtDNA analysis--namely, patients with the 11778 or with the 3460 mutation and patients without these primary mutations. Fifty nine per cent of patients had neurological abnormalities but there was no significant difference between the three groups. Movement disorders were the most common finding; nine patients had constant postural tremor, one chronic motor tic disorder, and one parkinsonism with dystonia. Four patients had peripheral neuropathy with no other evident cause. Two patients had a multiple sclerosis-like syndrome; in both patients MRI showed changes in the periventricular white matter. Thoracic kyphosis occurred in seven patients, five of whom had the 3460 mutation. In one patient the 3460 mutation was associated with involvement of the brain stem. It is suggested that various movement disorders, multiple sclerosis-like illness, and deformities of the vertebral column may associate pathogenetically with LHON.
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    We report the electron transfer properties of the NADH:ubiquinone oxidoreductase complex of the respiratory chain (Complex I) in mitochondria of cells derived from LHON patients with two different mutations in mitochondrial DNA (mtDNA). The mutations occur in the mtDNA genes coding for the ND1 and ND4 subunits of Complex I. The ND1/3460 mutation exhibits 80% reduction in rotenone-sensitive and ubiquinone-dependent electron transfer activity, whereas the proximal NADH dehydrogenase activity of the Complex is unaffected. This is in accordance with the proposal that the ND1 subunit interacts with rotenone and ubiquinone. In contrast, the ND4/11778 mutation had no effect on electron transfer activity of the Complex in inner mitochondrial membrane preparations; also K(m) for NADH and NADH dehydrogenase activity were unaffected. However, in isolated mitochondria with the ND4 mutation, the rate of oxidation of NAD-linked substrates, but not of succinate, was significantly decreased. This suggests that the ND4 subunit might be involved in specific aggregation of NADH-dependent dehydrogenases and Complex I, which may result in fast ('solid state') electron transfer from the former to the latter.
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  • Functional analysis of novel mutations in y(+)LAT-1 amino acid transporter gene causing lysinuric protein intolerance (LPI)

    Mykkanen, J   Torrents, D   Pineda, M   Camps, M   Yoldi, ME   Horelli-Kuitunen, N   Huoponen, K   Heinonen, M   Oksanen, J   Simell, O   Savontaus, ML   Zorzano, A   Palacin, M   Aula, P  

    Lysinuric protein intolerance (LPI; MIM 222700) is an autosomal recessive disorder characterized by defective transport of the cationic amino acids lysine, arginine and ornithine at the basolateral membrane of the polar epithelial cells in the intestine and renal tubules, and by hyperammonemia after high-protein meals, LPI is caused by mutations in the SLC7A7 (solute carrier family 7, member 7) gene encoding y(+)LAT-1 (y(+)L amino acid transporter-1), which co-induces together with 4F2 heavy chain (4F2hc) system y(+)L in Xenopus oocytes, All Finnish LPI patients share the same founder mutation 1181-2A-->T (LPIFin) not found in LPI patients elsewhere. Mutation screening of 20 non-Finnish LPI patients revealed 10 novel mutations: four deletions, two missense mutations, two nonsense mutations, a splice site mutation and a tandem duplication. Five LPI mutations (L334R, G54V, 1291delCTTT, 1548delC and LPIFin) were studied functionally, Ail mutant proteins failed to co-induce amino acid transport activity when expressed with 4F2hc in Xenopus oocytes, Immunostaining experiments revealed that frameshift mutants 1291delCTTT, 1548delC and LPIFin remained intracellular on expression with 4F2hc. In contrast, the missense mutants L334R and G54V reached the oocyte plasma membrane when coexpressed with 4F2hc, demonstrating that they are transport-inactivating mutations. This finding, together with the strong degree of conservation among all members of this family of amino acid transporters, indicates that residues L334 and G54 play a crucial role in the function of the y+LAT-1 transporter.
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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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  • Identification of an X-chromosomal locus and haplotype modulating the phenotype of a mitochondrial DNA disorder

    Hudson, G   Keers, S   Man, PYW   Griffiths, P   Huoponen, K   Savontaus, ML   Nikoskelainen, E   Zeviani, M   Carrara, F   Horvath, R   Karcagi, V   Spruijt, L   de Coo, IFM   Smeets, HJM   Chinnery, PF  

    Mitochondrial DNA (mtDNA) mutations are a major cause of human disease. A large number of different molecular defects ultimately compromise oxidative phosphorylation, but it is not clear why the same biochemical defect can cause diverse clinical phenotypes. There is emerging evidence that nuclear genes modulate the phenotype of primary mtDNA disorders. Here, we define an X-chromosomal haplotype that interacts with specific MTND mutations to cause visual failure in the most common mtDNA disease, Leber hereditary optic neuropathy. This effect is independent of the mtDNA genetic background and explains the variable penetrance and sex bias that characterizes this disorder.
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