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Mari Auranen Emil Ylikallio Jussi Toppila Mirja Somer Sari Kiuru-Enari Henna Tyynismaa 《Neurogenetics》2013,14(2):123-132
We describe a founder mutation in the gene encoding ganglioside-induced differentiation associated-protein 1 (GDAP1), leading to amino acid change p.H123R, as a common cause of autosomal dominant axonal Charcot-Marie-Tooth (CMT2) neuropathy in Finland. The mutation explains up to 14 % of CMT2 in Finland, where most patients with axonal neuropathy have remained without molecular diagnosis. Only three families out of 28 were found to carry putative disease mutations in the MFN2 gene encoding mitofusin 2. In addition, the MFN2 variant p.V705I was commonly found in our patients, but we provide evidence that this previously described mutation is a common polymorphism and not pathogenic. GDAP1-associated polyneuropathy caused predominantly a mild and slowly progressive phenotype. Besides distal leg muscle weakness, most patients showed mild proximal weakness, often with asymmetry and pes cavus. Our findings broaden the understanding of GDAP1 mutations in CMT2 phenotypes and provide support for the use of whole-exome sequencing in CMT gene diagnostics. 相似文献
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Mutant mitochondrial helicase Twinkle causes multiple mtDNA deletions and a late-onset mitochondrial disease in mice
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Tyynismaa H Mjosund KP Wanrooij S Lappalainen I Ylikallio E Jalanko A Spelbrink JN Paetau A Suomalainen A 《Proceedings of the National Academy of Sciences of the United States of America》2005,102(49):17687-17692
Defects of mitochondrial DNA (mtDNA) maintenance have recently been associated with inherited neurodegenerative and muscle diseases and the aging process. Twinkle is a nuclear-encoded mtDNA helicase, dominant mutations of which cause adult-onset progressive external ophthalmoplegia (PEO) with multiple mtDNA deletions. We have generated transgenic mice expressing mouse Twinkle with PEO patient mutations. Multiple mtDNA deletions accumulate in the tissues of these mice, resulting in progressive respiratory dysfunction and chronic late-onset mitochondrial disease starting at 1 year of age. The muscles of the mice faithfully replicate all of the key histological, genetic, and biochemical features of PEO patients. Furthermore, the mice have progressive deficiency of cytochrome c oxidase in distinct neuronal populations. These "deletor" mice do not, however, show premature aging, indicating that subtle accumulation of mtDNA deletions and progressive respiratory chain dysfunction are not sufficient to accelerate aging. This model is a valuable tool for therapy development and testing for adult-onset mitochondrial disorders. 相似文献
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Sainio Markus T. Välipakka Salla Rinaldi Bruno Lapatto Helena Paetau Anders Ojanen Simo Brilhante Virginia Jokela Manu Huovinen Sanna Auranen Mari Palmio Johanna Friant Sylvie Ylikallio Emil Udd Bjarne Tyynismaa Henna 《Journal of neurology》2019,266(2):353-360
Journal of Neurology - To describe adult-onset limb-girdle-type muscular dystrophy caused by biallelic variants in the PYROXD1 gene, which has been recently linked to early-onset congenital... 相似文献
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1 The effects of methyldopa withdrawal on liver function and drug metabolism were investigated in ten elderly females suffering from the drug-induced orthostatic reaction and resistant hypertension. 2 There was a significant increase in serum albumin level, antipyrine metabolism and urinary excretion of D-glucaric acid 6 months after the methyldopa withdrawal. 3 The results suggest that patients treated with methyldopa might show a reduced metabolizing ability in spite of normal liver function tests. 相似文献
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Kristin Samuelsson PhD MD Ana Radovic MD Rayomand Press PhD MD Mari Auranen PhD MD Emil Ylikallio PhD MD Henna Tyynismaa PhD Mikko KäRppä PhD MD Matilda Veteläinen MD Niina Peltola MD Svein Ivar Mellgren PhD MD Åse Mygland PhD MD Chantal Tallaksen PhD MD Henning Andersen PhD MD Astrid Juhl Terkelsen PhD MD Freja Fontain MD Aki Hietaharju PhD MD 《Muscle & nerve》2019,59(3):354-357
Introduction: In this study we assessed the value of genetic screening for Fabry disease (FD) and hereditary ATTR amyloidosis in patients with idiopathic small-fiber neuropathy (SFN) or mixed neuropathy in a clinical setting. Methods: This was a Nordic multicenter study with 9 participating centers. Patients with idiopathic SFN or mixed neuropathy were included. Genetic sequencing of the TTR and GLA genes was performed. Results: There were 172 patients enrolled in the study. Genetic screening was performed in 155 patients. No pathogenic mutations in the TTR gene were found. A single patient had a possible pathogenic variant, R118C, in the GLA gene, but clinical investigation showed no firm signs of FD. Discussion: Screening for hereditary ATTR amyloidosis and FD in patients with idiopathic SFN or mixed neuropathy without any additional disease-specific symptoms or clinical characteristics in a Nordic population appears to be of little value in a clinical setting. Muscle Nerve 59 :354–357, 2019 相似文献
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Emil Ylikallio Mridul Johari Svetlana Konovalova Jukka S Moilanen Sari Kiuru-Enari Mari Auranen Leila Pajunen Henna Tyynismaa 《European journal of human genetics : EJHG》2014,22(4):522-527
Charcot–Marie–Tooth disease (CMT) is a group of hereditary peripheral neuropathies. The dominantly inherited axonal CMT2 displays striking genetic heterogeneity, with 17 presently known disease genes. The large number of candidate genes, combined with lack of genotype–phenotype correlations, has made genetic diagnosis in CMT2 time-consuming and costly. In Finland, 25% of dominant CMT2 is explained by either a GDAP1 founder mutation or private MFN2 mutations but the rest of the families have remained without molecular diagnosis. Whole-exome and genome sequencing are powerful techniques to find disease mutations for CMT patients but they require large amounts of sequencing to confidently exclude heterozygous variants in all candidate genes, and they generate a vast amount of irrelevant data for diagnostic needs. Here we tested a targeted next-generation sequencing approach to screen the CMT2 genes. In total, 15 unrelated patients from dominant CMT2 families from Finland, in whom MFN2 and GDAP1 mutations had been excluded, participated in the study. The targeted approach produced sufficient sequence coverage for 95% of the 309 targeted exons, the rest we excluded by Sanger sequencing. Unexpectedly, the screen revealed a disease mutation only in one family, in the HSPB1 gene. Thus, new disease genes underlie CMT2 in the remaining families, indicating further genetic heterogeneity. We conclude that targeted next-generation sequencing is an efficient tool for genetic screening in CMT2 that also aids in the selection of patients for genome-wide approaches. 相似文献
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Emil Ylikallio Doyoun Kim Pirjo Isohanni Mari Auranen Eunjoon Kim Tuula L?nnqvist Henna Tyynismaa 《European journal of human genetics : EJHG》2015,23(10):1427-1430
Variants in family 1 kinesin (KIF1A), which encodes a kinesin axonal motor protein, have been described to cause variable neurological manifestations. Recessive missense variants have led to spastic paraplegia, and recessive truncations to sensory and autonomic neuropathy. De novo missense variants cause developmental delay or intellectual disability, cerebellar atrophy and variable spasticity. We describe a family with father-to-son transmission of de novo variant in the KIF1A motor domain, in a phenotype of pure spastic paraplegia. Structural modeling of the predicted p.(Ser69Leu) amino acid change suggested that it impairs the stable binding of ATP to the KIF1A protein. Our study reports the first dominantly inherited KIF1A variant and expands the spectrum of phenotypes caused by heterozygous KIF1A motor domain variants to include pure spastic paraplegia. We conclude that KIF1A should be considered a candidate gene for hereditary paraplegias regardless of inheritance pattern. 相似文献
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Mitochondria are essential organelles with multiple functions, the most well known being the production of adenosine triphosphate (ATP) through oxidative phosphorylation (OXPHOS). The mitochondrial diseases are defined by impairment of OXPHOS. They are a diverse group of diseases that can present in virtually any tissue in either adults or children. Here we review the main molecular mechanisms of mitochondrial diseases, as presently known. A number of disease-causing genetic defects, either in the nuclear genome or in the mitochondria's own genome, mitochondrial DNA (mtDNA), have been identified. The most classical genetic defect causing mitochondrial disease is a mutation in a gene encoding a structural OXPHOS subunit. However, mitochondrial diseases can also arise through impaired mtDNA maintenance, defects in mitochondrial translation factors, and various more indirect mechanisms. The putative consequences of mitochondrial dysfunction on a cellular level are discussed. 相似文献
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