／【Ｋ：】Ｓｅｒｖｅｒ／１８０１０６５５ 新潟厚生連農業協同組合／本文／３０ｄ

五十嵐

０４３‐０４５2018.02.22 20.28

A sudden death case with myotonic dystrophy
厚生連医誌
providing the第２７single
巻 １号
gene mutation
４３〜４
５of２０
the１８
Na pump promoter gene（SCN５A）regarded as the cause of fatal cardiac arrhythmia

Case report

A sudden death case with myotonic dystrophy providing
the single gene mutation of the Na pump promoter gene（SCN５A）regarded as the cause of fatal cardiac arrhythmia
Nagaoka Central General Hospital, Department of Pathology,
Department of Genetic diagnosis（Chu-etsu genetic diagnosis study group）; Pathologist

Toshihiko Ikarashi
Background : In myotonic dystrophy the sudden deathhas been caused by fatal cardiac arrhythmia, basedon the abnormality of the genes of the Na pump.
We experienced an unexplained sudden death casewith myotonic dystrophy and studied the abnormality of Na pump gene（SCN５A）.
Case report : The case was hospitalized with acute cholecystitis but she was found dead on bed on the nextmorning. Her medical history included adult-type
myotonic dystrophy at ４９ y/o, old myocardial infarct treated coronary stent insertion at ５
７ y/o, local resection for the neuroendocrine tumor of theduodenum at ６０ y/o without recurrence. We were
not able to identify the cause of death after a dissection. Na pump gene（SCN５A）was studied withformalin-fixed paraffin-embedded specimens bypolymerase chain reaction-single strand conformational polymorphism（PCR - SSCP）and single nucleotide polymorphism（SNP）with restriction enzymes. She showed（C/C + T/C）type of SNP ofthe Na ion pump promoter gene（SCN５A）.
Conclusion：（C/C + T/C）type of SNP of the Na ionpump promoter gene（SCN５A）was confirmed,
which probably brought on fetal arrhythmia in thiscase.
Key words : Na pump gene, SCN５A, exon ７, exon １２,exon １８, exon ２０, promoter, single nucleotide
polymorphism（SNP）, T-１
０６２, T-１
４１８, C/C & T/C
type, myotonic dystrophy, sudden death, fatal cardiac arrhythmia, polymerase chain reaction-single
strand conformational polymorphism （ PCR SSCP）

Introduction
Many unexplained sudden deaths have been genetically studied（１−３）. In myotonic dystrophy the sudden death has been caused by fatal cardiac arrhythmia,
based on the abnormality of the genes of the Na+ ionpump（４−６）. We experienced a unexplained sudden deathcase with myotonic dystrophy. She showed（C/C + T/C）

type of single nucleotide polymorphism（SNP）of the Na
ion pump promoter gene（SCN５A）, which probably
brought on fetal arrhythmia（７−９）.

Case report
The case（SN１７-００９）was hospitalized with acutecholecystitis in ６２-year-old, and percutaneous transhepatic
biliary drainage（PTGBD）was conducted. On the nextmorning, she was found dead on bed. Her medical history
was as follows : adult-type myotonic dystrophy at ４９ y/o,myocardial infarct in anterior wall of left ventricle treatedwith coronary stent insertion in anterior descending
branch at ５
７ y/o, local resection for the neuroendocrine
tumor of the duodenum at ６０ y/o without recurrence. We
were not able to identify the cause of death in spite ofdissection.
Myotonic dystrophy is complicated with a cardiac
muscle lesion as well as a skeletal muscle lesion, and fatal
cardiac arrhythmia by the abnormality of the Na pumpgene is noted（５,６）．Na pump gene SCN５A was studied
with deoxyribonucleic acid（DNA）from the formalin-fixedparaffin-embedded materials. SCN５A exon ７, １２−１, １２−２, １８, ２０, and promoters around T-１４１
８ and T-１０６２
were examined by polymerase chain reaction-single strand
conformational polymorphism（PCR - SSCP）according to
the previous reports（１−３）. Single nucleotide polymorphism（SNP）with the restriction endonuclease was examined for promoters around T-１４１
８ and T-１０６２（７−９）.
The PCR amplification of promoters around T-１４１８ andT-１０６２ with primers based on Homo sapiens sodium
channel voltage-gated type V（SCN５A）gene, promoter region and exons（AY３１３１６３）of DNA Data Bank of Japan（DDBJ）：the primers（５ −＃６９１−７１０, ３ −＃８５０−８３０; ＃：base sequence on AY３１３１６３）for T-１４１８ and（５ −＃１０６１−１０８０, ３ −＃１１８０−１１６１）for T-１０６２,respectively（Fig. １）（７−９）. As for the PCR product ofpromoter T-１４１８ and T-１０６２, they were １６１ bp and １
２３bp, respectively. They were, furthermore, digested withrestriction endonuclease Ear I and HaeIII（Takara Co）（Fig.１）. The contents of the enzyme digestion consistedof sample ２μl, H２O １０．
９μl，
１０xBuffer １．
５μl, and en-― 43 ―

／【Ｋ：】Ｓｅｒｖｅｒ／１８０１０６５５ 新潟厚生連農業協同組合／本文／３０ｄ

厚生連医誌

第２７巻

五十嵐

０４３‐０４５2018.02.22 20.28

１号 ４
３〜４５ ２０１８zyme ０．
６μl, were incubated at ３
７ degrees Celsius, １２hours. The results showed that exon ７, １２−１, １２−２, １８,and ２０ were normal. About promoters T-１４１８ and T１０６２, only T-１
０６２ band was found after a restriction enzyme digestion. As a result, the SNP type of promoters T１４１８and T-１
０６２was（T or C）and C, respectively, probable haploids（C/C+T/C）（Fig.１−３）（７,８）.

Conclusion
The case with myotonic dystrophy showed unexplained sudden death. The possibility of fatal arrhythmic
frequently complicated in myotonic dystrophy was studied
with Na pump SCN５A genes. As a result, SNP（C/C +T/C）type of promoter around T-１
４１８ and T-１０６２ wasfound（７, ８）. It was reported that this SNP type was significantly complicated with cardiac arrhythmia, and ourcase of sudden death was affected with fatal cardiac arrhythmia.

における呼吸、循環関連遺伝子内の多型解析並びにその倫理的問題」心臓ナトリウムイオンチャネルコード遺伝子（SCN５A）プロモーター領域に存在する SNP 解析．厚生労働科学研究助成金（子ども家庭総合研究事業）「乳幼児突然死症候群（SIDS）における病態解明と臨床的対応および予防法開発とその普及啓発に関する研究」分担報告書．２００９；７０−３．
９．Homo sapiens sodium channel voltage-gated type V（SCN５A）gene, promoter region and exon１（AY３１３１６３），DNA Data Bank of Japan（DDBJ）, National
Institute of Genetics（NIG）．入手：URL : http : //getentry.ddbj.nig.ac.jp/getentry/na/AY３
１３１６３?filetype=html

和 文 抄録

症例報告
Na ポンプ遺伝子（SCN５A）プロモーター遺伝子の変異による致死性不整脈が突然死の原因と思われる筋強直性ジストロフィー突然死の１症例

References
１．Ikarashi T. Genetic analysis of the myocardial Na+pump α subunit gene SCN５A mutation in ７ cases ofsudden death among our ４２５ autopsy cases − genemutation was suggested in ４ cases out of ７ ones by
the polymerase chain reaction-single strand conformational polymorphism（PCR-SSCP）method. Niigata-kenKoseiren Med J２０１５；２４：１−４.
２．Ikarashi T. A case of the intrauterine fetal death（IUFD）in２
７-weeks of gestation induced by the mutation of myocardial Na+ pump α subunit gene SCN５A.
Niigata-ken Koseiren Med J２０１６；２５：１
１５−７．
３．森博愛．Brugada 症候群における遺伝子異常．入手：URL : http : //udatsu.vs１.jp/Bru̲１５.htm.
４．広正修一他．筋強直性ジストロフィー症８例の心臓電気性理学的検討．心臓１９８７；１
９：１
６８−７４．入手：URL : https : //www.jstage.jst.go.jp/article/shinzo
１９６９/１
９/２/１９̲pdf/-cchar/ja.
５．Freyermuth F et al. Splicing misregulation of SCN５A
contributes to cardiac-conduction delay and heart arrhythmia in myotonic dstrophy. Nature Communications/７:１
１０６７/DOI :１０.１
０３８/ncomm１
１０６７/www.nature.
com/naturecommunications. from : URL : http : //www.
̲shiga - med . ac . jp / hqmed１/ oshirase / oshirase％２０pdf /ncomms１
１０６７.２０
１６.pdf.
６．大阪大学大学院医学系研究科神経内科学筋疾患グループ．成人の筋ジストロフィーの不整脈の原因を解 明．入 手：URL : http : //resou.osaka-u.ac.jp/ja/research/２０１６/２０１６０４１８̲２.
７．Bezzina C.R. et al Common sodium channel promoter haplotype in Asian subjects underlies variability
in cardiac conduction. Circulation ２００６；１１３：３３８−４４.
８．的場梁次、中留真人．
「乳幼児突然死症候群症例長岡中央綜合病院、病理科、遺伝子診断室；病理医
いか らしとしひこ

五十嵐俊彦
背景：我々は、原因不明の突然死症例の遺伝子学的に原因追求してきた。成人型強直性筋ジストロ
フィー症例には突然死が多く、致死性不整脈が原因と考えられている。また、Na＋イオンポンプの遺伝子異常が指摘されている。今回、成人型筋ジストロファイーの原因不明の突然死を経験し、Na イオンポンプ遺伝子 SCN５A に関して検討した。
症例内容：６２才の女性で、急性胆嚢炎で入院し、Percutaneous transhepatic biliary drainage（PTGBD）が施行された（SN１７−００９）。翌朝、死因不明の突然死で発見された。既往歴は、４９才に成人型筋強直性ジストロフィー、５７才に心筋梗塞でステント挿入、６０才に十二指腸の神経内分泌腫
瘍で局所切除術を受けた。解剖にもかかわらず死因を特定できなかっ た。Na ポ ン プ SCN５A
遺伝子検査を実施した。プロモーターの一塩基多型（single nucleotide polymorphism, SNP）による（C/C + T/C）型が認められた。
結論：Na ポンプ SCN５A 遺伝子検査により、プロモーターの一塩基多型（SNP）上、（C/C + T/C）型が認められ、致死的不整脈が示唆された。
キーワード：Na ポンプ遺伝子、SCN５A、exon７，１２，１８，２０，
プロモーター、１塩基多型、T-１０６２、T-１４１８、C/C & T/C 型、筋強直性ジストロフィー、突然死、致死性不整脈、ポリメラーゼ連鎖反応、一本鎖高次構造多型、ホルマリン固定―パラフィン包埋検体― 44 ―

／【Ｋ：】Ｓｅｒｖｅｒ／１８０１０６５５ 新潟厚生連農業協同組合／本文／３０ｄ

五十嵐

０４３‐０４５2018.02.22 20.28

A sudden death case with myotonic dystrophy providing the single gene mutation of theNa pump promoter gene（SCN５A）regarded as the cause of fatal cardiac arrhythmia
promoterprimer
PCR productrestriction
enzymetype of haploid

5’3’-target bases
normal type
T/T
(rest of band)
C/C

T-1418#691-710#850-831
161bp
Ear I
ctctT/ca
ctctT/ca
ctctT/ca(-)

T-1062#1061-1080#1180-1161
123bp
Hae III
gg/Cc
ggTc
ggTc
(+)

ctctCca
(+)

gg/Cc
(-)

most frequently
found in normal
Japanese (75%)
frequently
found in normal
Japanese (25%)

T/C

ctctT/ca
gg/Cc
(-)
(-)
C/T
ctctCca
ggTc
(+)
(+)
haploid type: T࣭C/C pattern suggested conduction abnormality (7, 8)

Fig.１. Genetic characteristics of promoter T-１４１
８and T-１０６２

Fig.２. Electrophoresis of PCR products before treatment by restriction enzyme.
PCR products of exon７, promoter T-１０６２, T-１４１
８. CTL : normal control.

Fig.３. Posttreatment by enzyme.
PCR product persisted in promoter T-１４１８, suggested that base of＃１４１８ wasdiploid T or haploid T in sequence. PCR product was digested and lost in promoter T-１
０６２, suggested that base of＃１０６
２was only C.
（２０１８／０１／２５受付）― 45 ―