聚合酶γ基因（<italic style="font-style: italic">POLG</italic>）突变在中国汉族人口中可能罕见

杨坤芳; 孟琳懿; 张元凤; 杨永臣; 成鸿毅; 姜志虎; 张泓; 陈育才

doi:10.24920/003697

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聚合酶γ基因（POLG）突变在中国汉族人口中可能罕见

中国医学科学杂志（英文版） 2020年35卷第4期页码：350-356

Original Article | Updated：2024-04-10

- 聚合酶γ基因（POLG）突变在中国汉族人口中可能罕见
- Affiliations：
  
  1. 1Department of Neurology, Shanghai Children’s Hospital, Shanghai Jiao Tong University, Shanghai 200062, China
  2. 2Department of Pharmacy, Shanghai Children’s Hospital, Shanghai Jiao Tong University, Shanghai 200062, China
  3. 3Clinical Laboratory, Shanghai Children’s Hospital, Shanghai Jiao Tong University, Shanghai 200062, China
- Author bio：
  
  * E-mail: chenyc@shchildren.com.cn; Tel: 86-21-62474880.
- Funds：
- DOI：10.24920/003697
  中图分类号：
- 收稿日期：2019-12-13，
  
  录用日期：2020-5-12，
  
  网络出版日期：2020-12-31，
  
  纸质出版日期：2020-12-31
- Accepted：
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杨坤芳, 孟琳懿, 张元凤, 等. 聚合酶γ基因（POLG）突变在中国汉族人口中可能罕见[J]. 中国医学科学杂志（英文版）, 2020,35(4):350-356.

Yang Kunfang, Meng Linyi, Zhang Yuanfeng, et al. POLG Mutations Are Probably Rare in the Han Chinese Population[J]. Chinese medical sciences journal, 2020, 35(4): 350-356.
杨坤芳, 孟琳懿, 张元凤, 等. 聚合酶γ基因（POLG）突变在中国汉族人口中可能罕见[J]. 中国医学科学杂志（英文版）, 2020,35(4):350-356. DOI： 10.24920/003697.

Yang Kunfang, Meng Linyi, Zhang Yuanfeng, et al. POLG Mutations Are Probably Rare in the Han Chinese Population[J]. Chinese medical sciences journal, 2020, 35(4): 350-356. DOI： 10.24920/003697.

摘要

目的

聚合酶γ基因（ploymerase gamma gene

POLG

）突变被认为是儿童和成人早期和青少年发作的非综合征性难治性癫痫的重要原因。本文通过基因测序探讨中国汉族癫痫患者中

POLG

致病性突变体的发生率/流行率。

方法

选取上海市儿童医院2015-2019年在丙戊酸钠（valproic acid

VPA）暴露前有癫痫发作的中国汉族患者

临床诊断标准基于国际抗癫痫联盟2014年癫痫共识声明。在VPA治疗前采集患者血液样本

采用一代或二代测序（next generation sequencing

NGS）方法对

POLG

基因进行测序

对

POLG

变异体进行评估。VPA治疗后随访2-3个月观察患者肝功能变化评价是否出现VPA毒性。

结果

216例中国汉族患者

年龄1个月~15岁

男102例

女114例。癫痫发病年龄1个月~13岁

病程2周~3年左右。由于全面性或顽固性部分性癫痫发作

他们按标准剂量服用VPA。没有患者在服用VPA后出现肝脏毒性。测序数据显示没有患者出现

POLG

纯合突变或复合杂合子突变。有2例患者检测出有c.1150G

T和p.D384Y单杂合子突变

1例患者有c.156μu_158dupGCA单杂合子突变

均无临床意义。

结论

本研究未发现功能修饰

POLG

纯合子突变和复合杂合子突变

VPA毒性在本研究中未见。

POLG

突变频率在汉族人群中可能很少见

VPA治疗剂量对汉族中国人可能相对安全。

Abstract

Objective

Mutations in polymerase gamma gene (

POLG)

are believed to be an important cause of early and juvenile onset of non-syndromic intractable epilepsy. The aim of this study is to investigate the incidence/prevalence of

POLG

pathogenic variants in epilespy patients of Han population through sequencing it.

Methods

Han Chinese patients with seizures prior valproic acid (VPA) exposure at Shanghai Children’s Hospital were collected from 2015 to 2019. The clinical diagnosis was based on the 2014 Consensus Statement of Epilepsy by the International League against Epilepsy (ILAE). Blood sampling were performed before VPA treatment. The

POLG

gene DNA was sequenced by either the first or the next generation sequencing (NGS). The

POLG

variant burden was illustrated. Liver functions were tested to describe whether they experienced VPA toxicity.

Results

Totally 216 Han Chinese patients were included

aged from 1 month to 15 years old

102 were male and 114 were female. The onset age was 1 month old to 13 years old

and the epilepsy course ranged from 2 weeks to about 3 years. VPA treatment was delivered for the generalized or intractable partial seizures at standard dosage. No patient experienced hepatic toxicity following VPA exposure. DNA sequencing data showed no patient had either a homozygous mutation or compound heterozygous mutation of

POLG

. Single heterozygous mutations of c.1150G

T and p.D384Y were found in 2 patients

and single heterozygous mutation of c.156_158dupGCA was found in 1 patient. None of these variants showed clinical significance.

Conclusions

Functional modifying

POLG

homozygous mutations and compound heterozygous mutations were not detected and VPA toxicity was not seen in the current study.

POLG

mutation frequency might be rare in Han Chinese

and standard VPA therapeutic dosage might be safe for Han Chinese patients.

关键词

Keywords

references

Bialer M . Why are antiepileptic drugs used for nonepileptic conditions? Epilepsia 2012 ; 53 ( 7 ): 26 - 33 . doi: 10.1111/j.1528-1167.2012.03712.x 10.1111/j.1528-1167.2012.03712.x .

Goldstein A , Bhatia P , Vento JM . Update on nuclear mitochondrial genes and neurologic disorders . Semin Pediatr Neurol 2012 ; 19 ( 4 ): 181 - 93 . doi: 10.1016/j.spen.2012.09.005 10.1016/j.spen.2012.09.005 . https://www.ncbi.nlm.nih.gov/pubmed/23245551 https://www.ncbi.nlm.nih.gov/pubmed/23245551

Long X , Wang X , Chen Y , et al . Polymorphisms in POLG were associated with the prognosis and mtDNA content in hepatocellular carcinoma patients . Bull Cancer 2017 ; 104 ( 6 ): 500 - 7 . doi: 10.1016/j.bulcan.2017.02.005 10.1016/j.bulcan.2017.02.005 . https://www.ncbi.nlm.nih.gov/pubmed/28457473 https://www.ncbi.nlm.nih.gov/pubmed/28457473

London F , Hadhoum N , Outteryck O , et al . Late-onset of Alpers-Huttenlocer syndrome: an unusual cause of refractory epilepsy and liver failure . Acta Neurol Belg 2017 ; 117 ( 1 ): 399 - 401 . doi: 10.1007/s13760-016-0672-8 10.1007/s13760-016-0672-8 . https://www.ncbi.nlm.nih.gov/pubmed/27422324 https://www.ncbi.nlm.nih.gov/pubmed/27422324

Stewart JD , Horvath R , Baruffini E , et al . Polymerase γ gene POLG determines the risk of sodium valproate-induced liver toxicity . Hepatology 2010 ; 52 ( 5 ): 1791 - 6 . doi: 10.1002/hep.23891 10.1002/hep.23891 . DOI: 10.1002/hep.23891 http://doi.org/10.1002/hep.23891 https://www.ncbi.nlm.nih.gov/pubmed/21038416 https://www.ncbi.nlm.nih.gov/pubmed/21038416

Hayhurst H , Anagnostou ME , Bogle HJ , et al . Dissecting the neuronal vulnerability underpinning Alpers’ syndrome: a clinical and neuropathological study . Brain Pathol 2019 ; 29 ( 1 ): 97 - 113 . doi: 10.1111/bpa.12640 10.1111/bpa.12640 . DOI: 10.1111/bpa.12640 http://doi.org/10.1111/bpa.12640 https://www.ncbi.nlm.nih.gov/pubmed/30021052 https://www.ncbi.nlm.nih.gov/pubmed/30021052

Lim A , Thomas RH . The mitochondrial epilepsia . Eur J Paediatr Neurol 2020 ; 24 : 47 - 52 . doi: 10.1016/j.ejpn.2019.12.021 10.1016/j.ejpn.2019.12.021 . DOI: 10.1016/j.ejpn.2019.12.021 http://doi.org/10.1016/j.ejpn.2019.12.021 https://www.ncbi.nlm.nih.gov/pubmed/31973983 https://www.ncbi.nlm.nih.gov/pubmed/31973983

Dreifuss FE , Santilli N , Langer DH . Valproic acid hepatic fatalities: a retrospective review . Neurology 1987 ; 37 ( 3 ): 379 - 85 . doi: 10.1212/wnl.37.3.379 10.1212/wnl.37.3.379 . DOI: 10.1212/wnl.37.3.379 http://doi.org/10.1212/wnl.37.3.379 https://www.ncbi.nlm.nih.gov/pubmed/3102998 https://www.ncbi.nlm.nih.gov/pubmed/3102998

International League Against Epilepsy . Definition of epilepsy 2014 . Available from https://www.ilae.org/guidelines/definition-and-classification/definition-of-epilepsy-2014. Accessed: December 15, 2019. https://www.ilae.org/guidelines/definition-and-classification/definition-of-epilepsy-2014 https://www.ilae.org/guidelines/definition-and-classification/definition-of-epilepsy-2014

Zeng K , Wang X , Xi Z , et al . Adverse effects of carbamazepine, phenytoin, valproate and lamotrigine monotherapy in epileptic adult Chinese patients . Clin Neurol Neurosurg 2010 ; 112 ( 4 ): 291 - 5 . doi: 10.1016/j.clineuro.2009.12.014 10.1016/j.clineuro.2009.12.014 . DOI: 10.1016/j.clineuro.2009.12.014 http://doi.org/10.1016/j.clineuro.2009.12.014 https://www.ncbi.nlm.nih.gov/pubmed/20071075 https://www.ncbi.nlm.nih.gov/pubmed/20071075

Zimmerman HJ , Ishak KG . Antiepileptic drugs . Drug-Induced Hepatotoxicity 1996 ; 121 ( 1 ): 637 - 62 . doi: 10.1007%2F978-3-642-61013-4_26 10.1007%2F978-3-642-61013-4_26 .

Krasich R , Copeland WC . DNA polymerases in the mitochondria: A critical review of the evidence . Front Biosci (Landmark Ed) 2017 ; 22 : 692 - 709 . doi: 10.2741/4510 10.2741/4510 . DOI: 10.2741/4510 http://doi.org/10.2741/4510 https://www.bioscience.org/2017/v22/af/4510/list.htm https://www.bioscience.org/2017/v22/af/4510/list.htm

Rahman S , Copeland WC . POLG-related disorders and their neurological manifestations . Nat Rev Neurol 2019 ; 15 ( 1 ): 40 - 52 . doi: 10.1038/s41582-018-0101-0 10.1038/s41582-018-0101-0 . DOI: 10.1038/s41582-018-0101-0 http://doi.org/10.1038/s41582-018-0101-0 https://www.ncbi.nlm.nih.gov/pubmed/30451971 https://www.ncbi.nlm.nih.gov/pubmed/30451971

Park S , Kang HC , Lee JS , et al . Alpers-huttenlocher syndrome first presented with hepatic failure: can liver transplantation be considered as treatment option? Pediatr Gastroenterol Hepatol Nutr 2017 ; 20 ( 4 ): 259 - 62 . doi: 10.5223/pghn.2017.20.4.259 10.5223/pghn.2017.20.4.259 . https://www.ncbi.nlm.nih.gov/pubmed/29302508 https://www.ncbi.nlm.nih.gov/pubmed/29302508

Jafarian I , Eskandari MR , Mashayekhi V , et al . Toxicity of valproic acid in isolated rat liver mitochondria . Toxicol Mech Methods 2013 ; 23 ( 8 ): 617 - 23 . doi: 10.3109/15376516.2013.821567 10.3109/15376516.2013.821567 . https://www.ncbi.nlm.nih.gov/pubmed/23819490 https://www.ncbi.nlm.nih.gov/pubmed/23819490

Hikmat O , Eichele T , Tzoulis C , et al . Understanding the epilepsy in POLG related disease . Int J Mol Sci 2017 ; 18 ( 9 ): 1845 . doi: 10.3390/ijms18091845 10.3390/ijms18091845 . DOI: 10.3390/ijms18091845 http://doi.org/10.3390/ijms18091845 http://www.mdpi.com/1422-0067/18/9/1845 http://www.mdpi.com/1422-0067/18/9/1845

Anagnostou ME , Ng YS , Robert W , et al . Epilepsy due to mutations in the mitochondrial polymerase gamma(POLG) gene: A clinical and molecular genetic review . Epilepsia 2016 ; 57 ( 10 ): 1531 - 45 . doi: 10.1111/epi.13508 10.1111/epi.13508 . DOI: 10.1111/epi.13508 http://doi.org/10.1111/epi.13508 https://www.ncbi.nlm.nih.gov/pubmed/27554452 https://www.ncbi.nlm.nih.gov/pubmed/27554452

Piekutowska-Abramczuka D , Kaliszewska M , Sułek A , et al . The frequency of mitochondrial polymerase gamma related disorders in a large Polish population cohort . Mitochondrion 2019 ; 47 : 179 - 87 . doi: 10.1016/j.mito.2018.11.004 10.1016/j.mito.2018.11.004 . DOI: 10.1016/j.mito.2018.11.004 http://doi.org/10.1016/j.mito.2018.11.004 https://www.ncbi.nlm.nih.gov/pubmed/30423451 https://www.ncbi.nlm.nih.gov/pubmed/30423451

Chan SS , Longley MJ , Copeland WC , et al . Modulation of the W748S mutation in DNA polymerase gamma by the E1143G polymorphismin mitochondrial disorders . Hum Mol Genet 2006 ; 15 ( 23 ): 3473 - 83 . doi: 10.1093/hmg/ddl424 10.1093/hmg/ddl424 . DOI: 10.1093/hmg/ddl424 http://doi.org/10.1093/hmg/ddl424 https://www.ncbi.nlm.nih.gov/pubmed/17088268 https://www.ncbi.nlm.nih.gov/pubmed/17088268

Van Geothem G , Martin JJ , Dermaut B , et al . Recessive POLG mutations presenting with sensory and ataxic neuropathy in compound heterozygote patients with progressive external ophthalmoplegia . Neuromuscul Disord 2003 ; 13 ( 2 ): 133 - 42 . doi: 10.1016/s0960-8966(02)00216-x 10.1016/s0960-8966(02)00216-x . DOI: 10.1016/s0960-8966(02)00216-x http://doi.org/10.1016/s0960-8966(02)00216-x https://www.ncbi.nlm.nih.gov/pubmed/12565911 https://www.ncbi.nlm.nih.gov/pubmed/12565911

Hakonen AH , Heiskanen S , Juvonen V , et al . Mitochondrial DNA polymerase W748S mutation: a common cause of autosomal recessive ataxia with ancient European origin . Am J Hum Genet 2005 ; 77 ( 3 ): 430 - 41 .doi: 10.1086/444548 10.1086/444548 . DOI: 10.1086/444548 http://doi.org/10.1086/444548 https://www.ncbi.nlm.nih.gov/pubmed/16080118 https://www.ncbi.nlm.nih.gov/pubmed/16080118

Winterthun S , Ferrari G , He L , et al . Autosomal recessive mitochondrialataxic syndrome due to mitochondrial polymerase gamma mutations . Neurology 2005 ; 64 ( 7 ): 1204 - 8 . doi: 10.1212/01.WNL.0000156516.77696.5A 10.1212/01.WNL.0000156516.77696.5A . DOI: 10.1212/01.WNL.0000156516.77696.5A http://doi.org/10.1212/01.WNL.0000156516.77696.5A https://www.ncbi.nlm.nih.gov/pubmed/15824347 https://www.ncbi.nlm.nih.gov/pubmed/15824347

Hakonen AH , Davidzon G , Salemi R , et al . Abundance of the POLG disease mutations in Europe, Australia, New Zealand and the United States explained by single ancient European founders . Eur J Human Genet 2007 ; 15 ( 7 ): 779 - 83 . doi: 10.1038/sj.ejhg.5201831 10.1038/sj.ejhg.5201831 . DOI: 10.1038/sj.ejhg.5201831 http://doi.org/10.1038/sj.ejhg.5201831 https://doi.org/10.1038/sj.ejhg.5201831 https://doi.org/10.1038/sj.ejhg.5201831

Da Pozzo P , Rubegni A , Rufa A , et al . Sporadic PEO caused by a novel POLG variation and a Twinkle mutation: digenic inheritance? Neruol Sci 2015 ; 36 ( 9 ): 1713 - 5 . doi: 10.1007/s10072-015-2247-5 10.1007/s10072-015-2247-5 .

Heidari MM , Houshmand M , Hosseinkhani S , et al . Association between trinucleotide CAG repeats of the DNA polymerase gene (POLG) with age of onset of Iranian Friedreich’s ataxia patients . Neurol Sci 2008 ; 29 ( 6 ): 489 - 93 . doi: 10.1007/s10072-008-1026-y 10.1007/s10072-008-1026-y . DOI: 10.1007/s10072-008-1026-y http://doi.org/10.1007/s10072-008-1026-y http://www.springerlink.com/content/l2454m434340102r/ http://www.springerlink.com/content/l2454m434340102r/

Ma L , Mao W , Xu E , et al . Novel POLG mutation in a patient with early-onset parkinsonism, progressive external ophthalmoplegia and optic atrophy . Int J Neurosci 2020 ; 130 ( 4 ): 319 - 21 . doi: 10.1080/00207454.2019.1681422 10.1080/00207454.2019.1681422 . https://www.ncbi.nlm.nih.gov/pubmed/31613174 https://www.ncbi.nlm.nih.gov/pubmed/31613174

Bindu PS , Govindaraju C , Sonam K , et al . Peripheral neuropathy in genetically characterized patients with mitochondrial disorders: A study from south India . Mitochondrion 2016 ; 27 : 1 - 5 . doi: 10.1016/j.mito.2015.12.009 10.1016/j.mito.2015.12.009 . DOI: 10.1016/j.mito.2015.12.009 http://doi.org/10.1016/j.mito.2015.12.009 https://www.ncbi.nlm.nih.gov/pubmed/26762927 https://www.ncbi.nlm.nih.gov/pubmed/26762927

Wang D , Li GD , Fan Y , et al . The mtDNA replication-related genes TFAM and POLG are associated with leprosy in Han Chinese from Southwest China . J Dermatol Sci 2017 ; 88 ( 3 ): 349 - 56 . doi: 10.1016/j.jdermsci.2017.09.001 10.1016/j.jdermsci.2017.09.001 . DOI: 10.1016/j.jdermsci.2017.09.001 http://doi.org/10.1016/j.jdermsci.2017.09.001 https://www.ncbi.nlm.nih.gov/pubmed/28958595 https://www.ncbi.nlm.nih.gov/pubmed/28958595

Lee YC , Lu YC , Chang MH , et al . Common mitochondrial DNA and POLG1 mutations are rare in the Chinese patients with adult-onset ataxia on Taiwan . J Neurol Sci 2007 ; 254 ( 1-2 ): 65 - 8 . doi: 10.1016/j.jns.2007.01.005 10.1016/j.jns.2007.01.005 . DOI: 10.1016/j.jns.2007.01.005 http://doi.org/10.1016/j.jns.2007.01.005 https://www.ncbi.nlm.nih.gov/pubmed/17300808 https://www.ncbi.nlm.nih.gov/pubmed/17300808

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聚合酶γ基因（POLG）突变在中国汉族人口中可能罕见

DOI：10.24920/003697

摘要

Abstract

关键词

Keywords

references