QT延長症候群2型においてKCNH2の非ミスセンス変異キャリアは比較的良好な予後を示す

京都大学新制・課程博士博士(医学)甲第24802号医博第4994号新制||医||1067(附属図書館)京都大学大学院医学研究科医学専攻(主査)教授 石見 拓, 教授 近藤 尚己, 教授 湊谷 謙司学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDFA

Impact of catheter ablation for atrial fibrillation on cardiac disorders in patients with coexisting heart failure

AIMS: We sought to investigate the time course of cardiac disorders after catheter ablation for atrial fibrillation (AF) in patients with coexisting heart failure (HF) during long-term follow-up. METHODS AND RESULTS: We analysed consecutive 280 patients undergoing first-time catheter ablation for AF who had coexisting HF, which was defined as prior HF hospitalization, estimated right ventricular systolic pressure ≥45 mmHg, or B-type natriuretic peptide (BNP) ≥200 pg/dL before the procedure. The primary endpoints were improvements in left ventricular ejection fraction (LVEF), E/e', BNP, left atrial dimension (LAD), and mitral regurgitation (MR) at 1 year. The secondary endpoints were serial changes of LVEF, E/e', BNP, LAD, and MR at 6 months, 1 year, and 5 years and cumulative incidence of HF hospitalization. During the mean follow-up of 5.1 ± 3.0 years, 70.7% of patients were free from recurrent AF. Among patients with LVEF < 50%, E/e' ≥ 15, BNP ≥ 200 pg/dL, LAD ≥ 40 mm, and moderate-to-severe MR, changes in those parameters from baseline to 1 year were 34.5 ± 9.9% to 43.2 ± 14.4% (P < 0.001), 19.7 ± 3.9 to 12.5 ± 6.6 (P < 0.001), 290 to 85 pg/dL (P < 0.001), and 100% to 37.8% (P < 0.001), respectively. The improvements in the cardiac disorders were maintained up to 5 years except for E/e'. In patients with LVEF < 40%, significant delayed improvement of LVEF beyond 1 year was observed (ΔLVEF = 10.5 ± 18.5, P = 0.001), but not in patients with LVEF of 40-49%. The cumulative incidence of HF hospitalization was 12.6% at 5 years. Baseline diastolic dysfunction was the only independent predictor for subsequent HF hospitalization. CONCLUSIONS: In patients undergoing AF ablation with coexisting HF, all cardiac disorders significantly improved after the procedure, which was mostly maintained during 5 year follow-up

Non-missense variants of KCNH2 show better outcomes in type 2 long QT syndrome

AIMS: More than one-third of type 2 long QT syndrome (LQT2) patients carry KCNH2 non-missense variants that can result in haploinsufficiency (HI), leading to mechanistic loss-of-function. However, their clinical phenotypes have not been fully investigated. The remaining two-thirds of patients harbour missense variants, and past studies uncovered that most of these variants cause trafficking deficiency, resulting in different functional changes: either HI or dominant-negative (DN) effects. In this study, we examined the impact of altered molecular mechanisms on clinical outcomes in LQT2 patients. METHODS AND RESULTS: We included 429 LQT2 patients (234 probands) carrying a rare KCNH2 variant from our patient cohort undergoing genetic testing. Non-missense variants showed shorter corrected QT (QTc) and less arrhythmic events (AEs) than missense variants. We found that 40% of missense variants in this study were previously reported as HI or DN. Non-missense and HI-groups had similar phenotypes, while both exhibited shorter QTc and less AEs than the DN-group. Based on previous work, we predicted the functional change of the unreported variants-whether they cause HI or DN via altered functional domains-and stratified them as predicted HI (pHI)- or pDN-group. The pHI-group including non-missense variants exhibited milder phenotypes compared to the pDN-group. Multivariable Cox model showed that the functional change was an independent risk of AEs (P = 0.005). CONCLUSION: Stratification based on molecular biological studies enables us to better predict clinical outcomes in the patients with LQT2

JASMINE: Near-infrared astrometry and time-series photometry science

The Japan Astrometry Satellite Mission for INfrared Exploration (JASMINE) is a planned M-class science space mission by the Institute of Space and Astronautical Science, the Japan Aerospace Exploration Agency. JASMINE has two main science goals. One is Galactic archaeology with a Galactic Center survey, which aims to reveal the Milky Way’s central core structure and formation history from Gaia-level (∼25 ${\mu}$as) astrometry in the near-infrared (NIR) Hw band (1.0–1.6 ${\mu}$m). The other is an exoplanet survey, which aims to discover transiting Earth-like exoplanets in the habitable zone from NIR time-series photometry of M dwarfs when the Galactic Center is not accessible. We introduce the mission, review many science objectives, and present the instrument concept. JASMINE will be the first dedicated NIR astrometry space mission and provide precise astrometric information on the stars in the Galactic Center, taking advantage of the significantly lower extinction in the NIR. The precise astrometry is obtained by taking many short-exposure images. Hence, the JASMINE Galactic Center survey data will be valuable for studies of exoplanet transits, asteroseismology, variable stars, and microlensing studies, including discovery of (intermediate-mass) black holes. We highlight a swath of such potential science, and also describe synergies with other missions

Mutations in Flk, FlgG, FlhA, and FlhE That Affect the Flagellar Type III Secretion Specificity Switch in Salmonella enterica▿

Upon completion of the flagellar hook-basal body (HBB) structure, the flagellar type III secretion system switches from secreting rod/hook-type to filament-type substrates. The secretion specificity switch has been reported to occur prematurely (prior to HBB completion) in flk-null mutants (P. Aldridge, J. E. Karlinsey, E. Becker, F. F. Chevance, and K. T. Hughes, Mol. Microbiol. 60:630-643, 2006) and in distal rod gene gain-of-function mutants (flgG* mutants) that produce filamentous rod structures (F. F. Chevance, N. Takahashi, J. E. Karlinsey, J. Gnerer, T. Hirano, R. Samudrala, S. Aizawa, and K. T. Hughes, Genes Dev. 21:2326-2335, 2007). A fusion of β-lactamase (Bla) to the C terminus of the filament-type secretion substrate FlgM was used to select for mutants that would secrete FlgM-Bla into the periplasmic space and show ampicillin resistance (Apr). Apr resulted from null mutations in the flhE gene, C-terminal truncation mutations in the flhA gene, null and dominant mutations in the flk gene, and flgG* mutations. All mutant classes required the hook length control protein (FliK) and the rod cap protein (FlgJ) for the secretion specificity switch to occur. However, neither the hook (FlgE) nor the hook cap (FlgD) protein was required for premature FlgM-Bla secretion in the flgG* and flk mutant strains, but it was in the flhE mutants. Unexpectedly, when deletions of either flgE or flgD were introduced into flgG* mutant strains, filaments were able to grow directly on the filamentous rod structures

Involvement of Illegitimate V(D)J Recombination or Microhomology-Mediated Nonhomologous End-Joining in the Formation of Intragenic Deletions of the Notch1 Gene in Mouse Thymic Lymphomas

Deregulated V(D)J recombination-mediated chromosomal rearrangements are implicated in the etiology of B- and T-cell lymphomagenesis. We describe here three pathways for the formation of the 5\u27 deletions of Notch1 gene in thymic lymphomas of wild-type or V(D)J recombination-defective scid mice. A pair of recombination signal sequence -like sequences composed of heptamer-like and nonamer-like motifs separated by 12- or 23-bp spacers (12- or 23-recombination signal sequence) were present in the vicinity of the deletion breakpoints in wild-type thymic lymphomas, accompanied by palindromic or nontemplated nucleotides at the junctions. In scid thymic lymphomas the deletions at the recombination signal sequence-like sequences occurred at a significantly lower frequency than in wild-type mice, whereas the deletions did not occur in Rag2-/- thymocytes. These results show that the 5\u27 deletions are formed by Rag-mediated V(D)J recombination machinery at cryptic recombination signal sequences in the Notch1 locus. In contrast, one third of the deletions in radiation-induced scid thymic lymphomas had microhomology at both ends, indicating that in the absence of DNA-dependent protein kinase-dependent nonhomologous end-joining, the microhomology-mediated nonhomologous endjoining pathway functions as a main mechanism to produce deletions. Furthermore the deletions were induced via a coupled pathway between Rag-mediated cleavage at cryptic recombination signal sequence and micronomology-mediated end-joining in radiation-induced scid thymic lymphomas. As the deletions at cryptic recombination signal sequence occur spontaneously, microhomology-mediated pathways might participate mainly in in radiation-induced lymphomagenesis. Recombination signal sequence-mediated deletions were present clonally in thymocyte population, suggesting that thymocytes with a 5\u27deletion of the Notch1 gene have a growth advantage and are involved in lymphomagenesis

Autonomous and FliK-Dependent Length Control of the Flagellar Rod in Salmonella enterica▿

Salmonella flgG point mutations produce filamentous rod structures whose lengths are determined by FliK. FliK length variants produce rods with lengths proportional to the corresponding FliK molecular size, suggesting that FliK controls the length of not only the hook but also the rod by the same molecular mechanism