Jun Akai
Tokyo Medical and Dental University
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FEBS Letters | 2000
Jun Akai; Naomasa Makita; Harumizu Sakurada; Nobumasa Shirai; Kazuo Ueda; Akira Kitabatake; Kiyoshi Nakazawa; Akinori Kimura; Masayasu Hiraoka
Mutations in the human cardiac Na+ channel α subunit gene (SCN5A) are responsible for Brugada syndrome, an idiopathic ventricular fibrillation (IVF) subgroup characterized by right bundle branch block and ST elevation on an electrocardiogram (ECG). However, the molecular basis of IVF in subgroups lacking these ECG findings has not been elucidated. We performed genetic screenings of Japanese IVF patients and found a novel SCN5A missense mutation (S1710L) in one symptomatic IVF patient that did not exhibit the typical Brugada ECG. Heterologously expressed S1710L channels showed marked acceleration in the current decay together with a large hyperpolarizing shift of steady‐state inactivation and depolarizing shift of activation. These findings suggest that SCN5A is one of the responsible genes for IVF patients who do not show typical ECG manifestations of the Brugada syndrome.
Cardiovascular Research | 2002
Nobumasa Shirai; Naomasa Makita; Koji Sasaki; Hisataka Yokoi; Ichiro Sakuma; Harumizu Sakurada; Jun Akai; Akinori Kimura; Masayasu Hiraoka; Akira Kitabatake
OBJECTIVE Loss of Na(+) channel function has been implicated in idiopathic ventricular fibrillation (IVF) and Brugada syndrome. We have studied the biophysical properties of an IVF mutation (S1710L) that exhibited an unusual clinical phenotype: rate-dependent bundle branch block without manifestation of Brugada-type ECG pattern. METHODS The mutant S1710L channels were expressed in mammalian cells and their gating properties, studied using whole-cell patch clamp techniques, were compared with wild-type (WT) and a Brugada syndrome mutant channel T1620M. RESULTS The S1710L channel exhibited significantly faster macroscopic current decay than WT or T1620M. In addition, S1710L showed a negative shift in the voltage-dependence of fast inactivation and slower recovery from fast inactivation than in WT or T1620M. In addition to the alterations in fast inactivation most commonly observed in Brugada syndrome mutations, S1710L exhibited marked enhancement in slow inactivation and a large positive shift of activation that potentially decreases conduction velocity. CONCLUSIONS These functional abnormalities may be responsible for the overlapping clinical phenotypes associated with Brugada syndrome and the cardiac conduction defect, a novel cardiac Na(+) channelopathy.
Human Genetics | 2000
Takuro Arimura; Takeyuki Nakamura; Shitoshi Hiroi; Manatsu Satoh; Megumi Takahashi; Nobuhisa Ohbuchi; Kazuo Ueda; Tatsuhito Nouchi; Noriko Yamaguchi; Jun Akai; Akira Matsumori; S Sasayama; Akinori Kimura
Abstract. Idiopathic dilated cardiomyopathy (IDC) is characterized by a thin-walled heart with systolic dysfunction of unknown etiology. Because abnormalities in genes for cytoskeletal proteins related to Z-disc function have recently been reported to cause IDC, genomic organization of the gene for nebulette, a novel actin-binding Z-disc protein, was determined and its sequence variations were searched for in Japanese patients with IDC and healthy controls. The nebulette gene consists of 28 exons, and four sequence variations leading to amino acid replacement (Gln187His, Met351Val, Asn654Lys, and Thr728Ala) were identified in the patients. These variations were also found in the healthy controls and hence they were polymorphisms and not disease-specific mutations. Frequencies of Gln187His, Met351Val, and Thr728Ala variants were similar in the patients and controls. However, the frequency of homozygotes for Lys at codon 654, a variant at a relatively conserved residue in an actin-binding motif, was significantly increased in nonfamilial IDC patients (n=106) as compared with healthy control subjects (n=331) (7.54% vs 1.21%, OR=6.25, P=0.002, 95% CI=1.92–20.29), while this association was not found in familial IDC patients (n=24). These observations suggest that the nebulette polymorphism in the actin-binding motif was a novel genetic marker of susceptibility to nonfamilial IDC.
International Journal of Cardiology | 1998
Akinori Kimura; Yasushi Kobayashi; Megumi Takahashi; Nobuhisa Ohbuchi; Hitoshi Kitamura; Takeyuki Nakamura; Manatsu Satoh; Taishi Sasaoka; Shitoshi Hiroi; Takuro Arimura; Jun Akai; Wulin Aerbajinai; Yukio Yasukochi; Fujio Numano
To further clarify the HLA-linked genes susceptible to arterio-vasculitis of unknown etiology, Takayasus arteritis and Buergers disease, polymorphism in the MICA gene, a newly identified gene near the HLA-B gene and expressed in epithelial cell lineage, was investigated. Polymerase chain reaction (PCR)-DNA conformation polymorphism (DCP) analysis and subsequent sequencing of the MICA gene have revealed that there are 5 MICA alleles which are different in the number of a GCT repeat in exon 5: MICA alleles MICA-1.1, -1.2, -1.3 and -1.4 have 9, 6, 5 and 4 GCT repeats, respectively, and MICA-1.5 has 5 GCT repeats with a 1 bp frameshift insertion in the repeat. MICA genotyping data in 81 Japanese patients with Takayasus arteritis, 38 Japanese patients with Buergers disease, and 160 healthy Japanese controls showed that MICA-1.2 and -1.4 were significantly associated with Takayasus arteritis and Buergers disease, respectively. Because MICA-1.2 and -1.4 were in strong linkage disequilibria with HLA-B52 and -B54 in the Japanese populations, respectively, we have compared the odds ratio (OR) of the risk to the diseases for individuals having both or each of the disease-associated MICA and HLA-B alleles. It was found that MICA-1.2 gave a significantly high OR of risk to Takayasus arteritis in the absence of HLA-B52, suggesting that the HLA-linked gene susceptible to Takayasus arteritis is mapped near the MICA gene. In contrast, MICA-1.4 gave a significantly high OR of risk to Buergers disease only in the presence of HLA-B54, suggesting that the HLA-linked gene susceptible to Buergers disease is linked to the HLA-B54-MICA-1.4 haplotype, and may be differently mapped from that to Takayasus arteritis.
Cell Biology International | 1998
Ryu-Ichiro Hata; Jun Akai; Akinori Kimura
In order to investigate possible cell positional effects on the gene expression of human dermal fibroblasts, the authors cultured the cells on non‐coated polystyrene culture dishes, type I collagen‐coated dishes, or collagen gels formed by type I collagen, or suspended them in type I collagen gels and measured collagen synthesis by the cells. The production rate of type I collagen was similar whether cells were cultured on non‐coated polystyrene or on type I collagen‐coated dishes, but it was suppressed significantly when the cells were placed within the collagen gel matrix. Time‐dependent expression of genes for α1(I) and α2(I) collagen chains was measured by Northern blot analysis. A significant increase in mRNA levels for these chains was observed when the cells were cultured for three days on type I collagen‐coated dishes or on collagen gels. On the other hand, a significant decrease in the mRNA levels was observed after 2 days and later, when the cells were cultured within type I collagen gel matrix. These results indicate that human dermal fibroblasts recognize their position on or in type I collagen (extracellular matrix) and respond by changing their expression patterns of type I collagen chain genes. The results of the kinetics of gene expression also suggest that upregulation and downregulation of type I collagen genes are controlled by different mechanisms.
Gene | 1999
Jun Akai; Akinori Kimura; Ryu-Ichiro Hata
Biochemical and Biophysical Research Communications | 2000
Ryu-Ichiro Hata; Jun Akai; Akinori Kimura; Osamu Ishikawa; Masataka Kuwana; Hiroshi Shinkai
Tissue Antigens | 2001
N. Obuchi; Megumi Takahashi; Tatsuhito Nouchi; Manatsu Satoh; Takuro Arimura; Kazuo Ueda; Jun Akai; Masao Ota; Taeko Naruse; Hidetoshi Inoko; Fujio Numano; Akinori Kimura
Genomics | 2001
Hidenobu Soejima; Shoko Kawamoto; Jun Akai; Osamu Miyoshi; Yuji Arai; Toshifumi Morohka; Shuzo Matsuo; Norio Niikawa; Akinori Kimura; Kousaku Okubo; Tsunehiro Mukai
Connective tissue | 1998
Jun Akai; Akinori Kimura; Katsuhiko Arai; Kohkichi Uehara; Ryu-Ichiro Hata