title: A novel missense mutation of RYR1 in familial idiopathic hyper CK-emia.
abstract: Persistent elevation of serum creatine kinase (CK) without any symptoms has been called idiopathic hyper CK-emia (IHCK). We examined a four-generation Japanese pedigree of familial IHCK. The multipoint linkage analysis of the pedigree showed seven clear peaks of logarithm of odds (LOD) scores (>1.4). By the exome sequencing followed by multiple filtering processes, we identified one novel heterozygous nonsynonymous single nucleotide variant (SNV), c.7034G>C, p.S2345T in the ryanodine receptor 1 gene, RYR1 cosegregated with IHCK in the pedigree. Mutation Taster predicted this substitution as "disease causing" (p=0.999). The PolyPhen-2 and PANTHER subPSEC scores for the substitution are 0.911 (possibly damaging) and -3.56 (probably damaging), respectively. We confirmed the absence of the SNV in 511 healthy Japanese individuals excluding the possibility of a normal variant with a very low frequency. Immunohistochemistry and Western blotting of biopsy samples consistently showed the expression level of RYR1 reduced in the patient. In real-time RT-PCR, the mRNA expression level of RYR1 was also significantly reduced in the patient (p=0.009). These results suggest that the novel nonsynonymous SNV contribute to the vulnerability of the RYR1 protein through the dominant negative effect. We conclude that the SNV in the RYR1 gene is one of the responsible genes of IHCK.
authors.affiliation: Division of Genomics, Medical Institute of Bioregulation, Kyushu University, Japan; Division of Respirology, Neurology and Rheumatology, Department of Medicine, Kurume University School of Medicine, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Sano
authors.affiliation: Division of Genomics, Medical Institute of Bioregulation, Kyushu University, Japan; Division of Respirology, Neurology and Rheumatology, Department of Medicine, Kurume University School of Medicine, Japan.
authors.forename: Shiroh
authors.initials: S
authors.lastname: Miura
authors.affiliation: Division of Genomics, Medical Institute of Bioregulation, Kyushu University, Japan.
authors.forename: Toshiya
authors.initials: T
authors.lastname: Fujiwara
authors.affiliation: Division of Genomics, Medical Institute of Bioregulation, Kyushu University, Japan.
authors.forename: Ryuta
authors.initials: R
authors.lastname: Fujioka
authors.affiliation: Division of Respirology, Neurology and Rheumatology, Department of Medicine, Kurume University School of Medicine, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Yorita
authors.affiliation: Division of Respirology, Neurology and Rheumatology, Department of Medicine, Kurume University School of Medicine, Japan.
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Noda
authors.affiliation: Division of Respirology, Neurology and Rheumatology, Department of Medicine, Kurume University School of Medicine, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kida
authors.affiliation: Division of Respirology, Neurology and Rheumatology, Department of Medicine, Kurume University School of Medicine, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Azuma
authors.affiliation: Division of Respirology, Neurology and Rheumatology, Department of Medicine, Kurume University School of Medicine, Japan.
authors.forename: Shinjiro
authors.initials: S
authors.lastname: Kaieda
authors.affiliation: Department of Medical Chemistry, Kurume University School of Medicine, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Yamamoto
authors.affiliation: Division of Respirology, Neurology and Rheumatology, Department of Medicine, Kurume University School of Medicine, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Taniwaki
authors.affiliation: Division of Genomics, Medical Institute of Bioregulation, Kyushu University, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Fukumaki
authors.affiliation: Division of Genomics, Medical Institute of Bioregulation, Kyushu University, Japan. Electronic address: hshibata@gen.kyushu-u.ac.jp.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Shibata
mesh_terms: D000818:Animals; D003402:Creatine Kinase / Q000097:blood*; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D008040:Genetic Linkage; D006801:Humans; D007564:Japan; D008297:Male; D008659:Metabolic Diseases / Q000097:blood* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal / Q000201:enzymology / Q000473:pathology; D020125:Mutation, Missense / Q000235:genetics*; D009431:Neural Conduction / Q000235:genetics; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics*
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; D003402:Creatine Kinase
keywords: Autosomal dominant; Creatine kinase; Exome sequencing; Hyper CK-emia; Malignant hyperthermia; Ryanodine receptor