Yasuko Ichihara

Malignant hyperthermia in Japan: mutation screening of the entire ryanodine receptor type 1 gene coding region by direct sequencing.

Background:Malignant hyperthermia (MH) is a disorder of calcium homeostasis in skeletal muscle triggered by volatile anesthetics or succinylcholine in susceptible persons. More than 100 mutations in the ryanodine receptor type 1 gene (RYR1) have been associated with MH susceptibility, central core disease, or both. RYR1 mutations may account for up to 70% of MH-susceptible cases. The authors aimed to determine the frequency and distribution of RYR1 mutations in the Japanese MH-susceptible population. Methods:The authors selected 58 unrelated Japanese diagnosed as MH-susceptible for having an enhanced Ca2+-induced Ca2+ release rate from the sarcoplasmic reticulum on chemically skinned muscle fibers. They sequenced the entire RYR1 coding region from genomic DNA. Muscle pathology was also characterized. Results:Seven previously reported and 26 unknown RYR1 potentially pathogenic sequence variations were identified in 33 patients (56.9%). Of these patients, 48% had cores on muscle biopsy. The mutation detection rate was higher in patients with clear enhancement of Ca2+-induced Ca2+ release rate (72.4%), whereas all patients with central core disease had RYR1 mutations. Six patients harbored potentially causative compound heterozygous sequence variations. Conclusions:Distribution and frequency of RYR1 mutations differed markedly from those of the North American and European MH-susceptible population. Comprehensive screening of the RYR1 gene is recommended for molecular investigations in MH-susceptible individuals, because many mutations are located outside the “hot spots.” Based on the observed occurrence of compound heterozygous state, the prevalence of a possibly predisposing phenotype in the Japanese population might be as high as 1 in 2,000 people.

Cytokine-Dependent Modification of IL-12p70 and IL-23 Balance in Dendritic Cells by Ligand Activation of Vα24 Invariant NKT Cells

CD1d-restricted invariant NKT (iNKT) cells play crucial roles in various types of immune responses, including autoimmune diseases, infectious diseases and tumor surveillance. The mechanisms underlying their adjuvant functions are well understood. Nevertheless, although IL-4 and IL-10 production characterize iNKT cells able to prevent or ameliorate some autoimmune diseases and inflammatory conditions, the precise mechanisms by which iNKT cells exert immune regulatory function remain elusive. This study demonstrates that the activation of human iNKT cells by their specific ligand α-galactosylceramide enhances IL-12p70 while inhibiting the IL-23 production by monocyte-derived dendritic cells, and in turn down-regulating the IL-17 production by memory CD4+ Th cells. The ability of the iNKT cells to regulate the differential production of IL-12p70/IL-23 is mainly mediated by a remarkable hallmark of their function to produce both Th1 and Th2 cytokines. In particular, the down-regulation of IL-23 is markedly associated with a production of IL-4 and IL-10 from iNKT cells. Moreover, Th2 cytokines, such as IL-4 and IL-13 play a crucial role in defining the biased production of IL-12p70/IL-23 by enhancement of IL-12p70 in synergy with IFN-γ, whereas inhibition of the IFN-γ-promoted IL-23 production. Collectively, the results suggest that iNKT cells modify the IL-12p70/IL-23 balance to enhance the IL-12p70-induced cell-mediated immunity and suppress the IL-23-dependent inflammatory pathologies. These results may account for the long-appreciated contrasting beneficial and adverse consequence of ligand activation of iNKT cells.

Additional evidence that the ryanodine receptor gene (RYR1) causes malignant hyperthermia and severe skeletal malformations.

Additional Evidence That the Ryanodine Receptor Gene (RYR1) Causes Malignant Hyperthermia and Severe Skeletal Malformations Yosuke Kakisaka, Kazuhiro Haginoya,* Yuko Takahashi, Tatsuhiro Ochiai, Ikuma Fujiwara, Atsuo Kikuchi, Keisuke Wakusawa, Satoru Kobayashi, Hirosato Kikuchi, Yasuko Ichihara, Shinichiro Takahashi, and Ichizo Nishino Department of Pediatrics, Tohoku University School of Medicine, Sendai, Japan Department of Pediatric Neurology, Takuto Rehabilitation Center for Children, Sendai, Japan Department of Orthopedics, Takuto Rehabilitation Center for Children, Sendai, Japan Department of Anesthesiology, Saitama Medical University Hospital, Saitama, Japan Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan