46 research outputs found

    Identification of RNF213 as a Susceptibility Gene for Moyamoya Disease and Its Possible Role in Vascular Development

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    もやもや病感受性遺伝子の特定とその機能についての発見. 京都大学プレスリリース. 2011-7-21.Background Moyamoya disease is an idiopathic vascular disorder of intracranial arteries. Its susceptibility locus has been mapped to 17q25.3 in Japanese families, but the susceptibility gene is unknown. Methodology/Principal Findings Genome-wide linkage analysis in eight three-generation families with moyamoya disease revealed linkage to 17q25.3 (P<10-4). Fine mapping demonstrated a 1.5-Mb disease locus bounded by D17S1806 and rs2280147. We conducted exome analysis of the eight index cases in these families, with results filtered through Ng criteria. There was a variant of p.N321S in PCMTD1 and p.R4810K in RNF213 in the 1.5-Mb locus of the eight index cases. The p.N321S variant in PCMTD1 could not be confirmed by the Sanger method. Sequencing RNF213 in 42 index cases confirmed p.R4810K and revealed it to be the only unregistered variant. Genotyping 39 SNPs around RNF213 revealed a founder haplotype transmitted in 42 families. Sequencing the 260-kb region covering the founder haplotype in one index case did not show any coding variants except p.R4810K. A case-control study demonstrated strong association of p.R4810K with moyamoya disease in East Asian populations (251 cases and 707 controls) with an odds ratio of 111.8 (P = 10−119). Sequencing of RNF213 in East Asian cases revealed additional novel variants: p.D4863N, p.E4950D, p.A5021V, p.D5160E, and p.E5176G. Among Caucasian cases, variants p.N3962D, p.D4013N, p.R4062Q and p.P4608S were identified. RNF213 encodes a 591-kDa cytosolic protein that possesses two functional domains: a Walker motif and a RING finger domain. These exhibit ATPase and ubiquitin ligase activities. Although the mutant alleles (p.R4810K or p.D4013N in the RING domain) did not affect transcription levels or ubiquitination activity, knockdown of RNF213 in zebrafish caused irregular wall formation in trunk arteries and abnormal sprouting vessels. Conclusions/Significance We provide evidence suggesting, for the first time, the involvement of RNF213 in genetic susceptibility to moyamoya disease

    Ataxic form of central pontine myelinolysis

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    Central pontine myelinolysis (CPM), a neurologic disorder caused most frequently by rapid correction of hyponatremia, is characterized by demyelination that affects the central portion of the base of the pons. Central pontine myelinolysis occurs frequently in alcoholism and chronic liver disease. Clinical features usually reflect damage to the descending motor tracts and include spastic tetraparesis, pseudobulbar paralysis and the locked-in syndrome. Cerebellar ataxia with out weakness and pyramidal signs is extremely unusual. There are only very few reports of central pontine myelinolysis presenting as cerebellar ataxia

    Rapid Eye Movement Sleep Deprivation Induces Neuronal Apoptosis by Noradrenaline Acting on Alpha1 Adrenoceptor and by Triggering Mitochondrial Intrinsic Pathway

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    Many neurodegenerative disorders are associated with rapid eye movement sleep (REMS)-loss, however the mechanism was unknown. As REMS-loss elevates noradrenaline (NA) level in the brain as well as induces neuronal apoptosis and degeneration, in this study we have delineated the intracellular molecular pathway involved in REMS deprivation (REMSD) associated NA-induced neuronal apoptosis. Rats were REMS deprived for 6 days by the classical flower-pot method, suitable controls were conducted and the effects on apoptosis markers evaluated. Further, the role of NA was studied by one, intraperitoneal (i.p.) injection of NA-ergic alpha1-adrenoceptor antagonist prazosin (PRZ) and two, by down-regulation of NA synthesis in locus coeruleus (LC) neurons by local microinjection of tyrosine hydroxylase siRNA (TH-siRNA). Immunoblot estimates showed that the expressions of pro-apoptotic proteins viz. Bcl2-associated death promoter (BAD) protein, apoptotic protease activating factor-1 (Apaf-1), cytochrome c, caspase9, caspase3 were elevated in the REMS-deprived rat brains, while caspase8 level remained unaffected; PRZ treatment did not allow elevation of these pro-apoptotic factors. Further, REMSD increased cytochrome c expression, which was prevented if the NA synthesis from the LC neurons was blocked by microinjection of TH-siRNA in vivo into the LC during REMSD in freely moving normal rats. Mitochondrial damage was re-confirmed by transmission electron microscopy (TEM), which showed distinctly swollen mitochondria with disintegrated cristae, chromosomal condensation and clumping along the nuclear membrane and all these changes were prevented in PRZ treated rats. Combining findings of this study along with earlier reports we propose that upon REMSD NA level increases in the brain as the LC NA-ergic REM-OFF neurons do not cease firing and TH is up-regulated in those neurons. This elevated NA acting on alpha1-adrenoceptors damages mitochondria causing release of cytochrome c to activate intrinsic pathway for inducing neuronal apoptosis in REMS deprived rat brain

    An interesting case of hemiplegia in a child

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    Hemiplegia in children occurs due to several causes. We report an interesting case who presented with prolonged fever, native valve endocarditis and infection triggered Macrophage activation syndrome. Macrophage activation syndrome (Hemophagocytic Lymphohistiocytosis syndrome) is a rare, potentially fatal inflammatory response syndrome characterized by fever, pancytopenia, rash, falling ESR, increased ferritin, increased triglycerides and hypofibrinogenemia. Central nervous system involvement is frequent with, seizures, irritability, stiff neck, cranial nerve palsy, ataxia and coma

    Triphenylphosphine promoted addition of dimethyl acetylenedicarboxylate to 1,2-benzoquinones: facile synthesis of novel γ-spirolactones

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    The addition of dimethyl acetylenedicarboxylate to o-quinones in the presence of triphenylphosphine leading to highly functionalised γ-spirolactones is reported

    Noninvasive Biomagnetic Detection of Isolated Ischemic Bowel Segments

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