TY - JOUR
T1 - A novel missense mutation of RYR1 in familial idiopathic hyper CK-emia
AU - Sano, Ken
AU - Miura, Shiroh
AU - Fujiwara, Toshiya
AU - Fujioka, Ryuta
AU - Yorita, Akiko
AU - Noda, Kazuhito
AU - Kida, Hiroshi
AU - Azuma, Koichi
AU - Kaieda, Shinjiro
AU - Yamamoto, Ken
AU - Taniwaki, Takayuki
AU - Fukumaki, Yasuyuki
AU - Shibata, Hiroki
N1 - Funding Information:
We thank all family members for their participation. We also thank Chitoshi Oki and Mayumi Yamamoto for their technical assistance. This work was supported by the Grant-in-Aid for Scientific Research on Innovative Areas “Exploring molecular basis for brain diseases based on personal genomics” (# 23129504 ) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. This work was partly performed in the Cooperative Research Project Program of the Medical Institute of Bioregulation, Kyushu University.
Publisher Copyright:
© 2015 Elsevier B.V.
PY - 2015/9/15
Y1 - 2015/9/15
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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84939252499&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84939252499&partnerID=8YFLogxK
U2 - 10.1016/j.jns.2015.06.035
DO - 10.1016/j.jns.2015.06.035
M3 - Article
C2 - 26119398
AN - SCOPUS:84939252499
VL - 356
SP - 142
EP - 147
JO - Journal of the Neurological Sciences
JF - Journal of the Neurological Sciences
SN - 0022-510X
IS - 1-2
M1 - 13864
ER -