A novel missense mutation of RYR1 in familial idiopathic hyper CK-emia

Ken Sano, Shiroh Miura, Toshiya Fujiwara, Ryuta Fujioka, Akiko Yorita, Kazuhito Noda, Hiroshi Kida, Koichi Azuma, Shinjiro Kaieda, Ken Yamamoto, Takayuki Taniwaki, Yasuyuki Fukumaki, Hiroki Shibata

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Abstract

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.

Original languageEnglish
Article number13864
Pages (from-to)142-147
Number of pages6
JournalJournal of the Neurological Sciences
Volume356
Issue number1-2
DOIs
Publication statusPublished - Sep 15 2015

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Missense Mutation
Creatine Kinase
Pedigree
Nucleotides
Genes
Exome
Ryanodine Receptor Calcium Release Channel
Real-Time Polymerase Chain Reaction
Western Blotting
Immunohistochemistry
Biopsy
Messenger RNA
Mutation
Serum
Proteins

All Science Journal Classification (ASJC) codes

  • Neurology
  • Clinical Neurology

Cite this

A novel missense mutation of RYR1 in familial idiopathic hyper CK-emia. / Sano, Ken; Miura, Shiroh; Fujiwara, Toshiya; Fujioka, Ryuta; Yorita, Akiko; Noda, Kazuhito; Kida, Hiroshi; Azuma, Koichi; Kaieda, Shinjiro; Yamamoto, Ken; Taniwaki, Takayuki; Fukumaki, Yasuyuki; Shibata, Hiroki.

In: Journal of the Neurological Sciences, Vol. 356, No. 1-2, 13864, 15.09.2015, p. 142-147.

Research output: Contribution to journalArticle

Sano, K, Miura, S, Fujiwara, T, Fujioka, R, Yorita, A, Noda, K, Kida, H, Azuma, K, Kaieda, S, Yamamoto, K, Taniwaki, T, Fukumaki, Y & Shibata, H 2015, 'A novel missense mutation of RYR1 in familial idiopathic hyper CK-emia', Journal of the Neurological Sciences, vol. 356, no. 1-2, 13864, pp. 142-147. https://doi.org/10.1016/j.jns.2015.06.035
Sano K, Miura S, Fujiwara T, Fujioka R, Yorita A, Noda K et al. A novel missense mutation of RYR1 in familial idiopathic hyper CK-emia. Journal of the Neurological Sciences. 2015 Sep 15;356(1-2):142-147. 13864. https://doi.org/10.1016/j.jns.2015.06.035
Sano, Ken ; Miura, Shiroh ; Fujiwara, Toshiya ; Fujioka, Ryuta ; Yorita, Akiko ; Noda, Kazuhito ; Kida, Hiroshi ; Azuma, Koichi ; Kaieda, Shinjiro ; Yamamoto, Ken ; Taniwaki, Takayuki ; Fukumaki, Yasuyuki ; Shibata, Hiroki. / A novel missense mutation of RYR1 in familial idiopathic hyper CK-emia. In: Journal of the Neurological Sciences. 2015 ; Vol. 356, No. 1-2. pp. 142-147.
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N2 - 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.

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