心肌致密化不全新致病基因的筛选及其表达特征变化

李红燕; 郭芸; 刘奥怡; 吕铁伟

doi:10.16016/j.2097-0927.202110035

您当前的位置：

首页 >

文章列表页 >

心肌致密化不全新致病基因的筛选及其表达特征变化

临床医学 | 更新时间：2026-01-09

- 心肌致密化不全新致病基因的筛选及其表达特征变化
- Screening for new causative genes and their expression profiles in patients with left ventricular noncompaction
- 陆军军医大学学报 2022年44卷第9期页码：913-922
- 作者机构：
  
  400014 重庆，重庆医科大学附属儿童医院心血管内科，国家儿童健康与疾病临床医学研究中心，儿童发育疾病研究教育部重点实验室，儿科学重庆市重点实验室
- 作者简介：
  
  [吕铁伟，E-mail: ltw200145@163.com LYU Tiewei, E-mail: ltw200145@163.com
- 基金信息：
  
  国家自然科学基金面上项目(81570218);国家自然科学基金面上项目(82170244);重庆市自然科学基金面上项目(cstc2020jcyj-msxmX0384)
- DOI：10.16016/j.2097-0927.202110035
  中图分类号： R394-33;R394.5;R542.2
- 收稿：2021-10-11，
  
  修回：2022-01-13，
  
  纸质出版：2022-05-15
- 稿件说明：
移动端阅览
李红燕, 郭芸, 刘奥怡, 等. 心肌致密化不全新致病基因的筛选及其表达特征变化[J]. 陆军军医大学学报, 2022,44(9):913-922.

Hongyan LI, Yun GUO, Aoyi LIU, et al. Screening for new causative genes and their expression profiles in patients with left ventricular noncompaction[J]. Journal of Army Medical University, 2022, 44(9): 913-922.
李红燕, 郭芸, 刘奥怡, 等. 心肌致密化不全新致病基因的筛选及其表达特征变化[J]. 陆军军医大学学报, 2022,44(9):913-922. DOI： 10.16016/j.2097-0927.202110035.

Hongyan LI, Yun GUO, Aoyi LIU, et al. Screening for new causative genes and their expression profiles in patients with left ventricular noncompaction[J]. Journal of Army Medical University, 2022, 44(9): 913-922. DOI： 10.16016/j.2097-0927.202110035.

摘要

目的

筛选心肌致密化不全(left ventricular noncompaction，LVNC)的致病基因并进行功能验证，为研究发病机制、遗传咨询和早期干预提供依据。

方法

收集自2018年1月至2020年12月于重庆医科大学附属儿童医院门诊就诊的3个LVNC家系的血液样本进行全外显子测序(whole-exome sequencing，WES)，得到3个家系均筛选出的可能致病基因，同时分别构建LVNC患者和正常人来源的诱导多能干细胞-心肌细胞(induced pluripotent stem cells-cardiomyocytes，iPSC-CMs)模型，收取不同时间点的细胞，采用实时荧光定量PCR (quantitative real-time PCR，qPCR)对上述基因进行验证，观察它们在诱导分化过程中的表达特征变化。

结果

WES筛选出3个LVNC家系共同的可能致病基因14个，qPCR检测结果提示这些基因在不同的时间点(0、10、20、30 d)表达量发生动态改变，并且在正常组及LVNC患者组间其表达量存在明显差异。

结论

3个LVNC家系通过WES筛选出的14个共同的可能致病基因，涉及影响细胞骨架、细胞极性、钙离子钾离子调节及能量代谢等方面。

Abstract

Objective

To screen the pathogenic genes in the patients with left ventricular noncompaction (LVNC) and validate their functions in order to provide references for pathogenesis

genetic counseling and early intervention of the disease.

Methods

Blood samples from 3 LVNC families attending the outpatient clinic of our hospital from January 2018 to December 2020 were collected for whole-exome sequencing (WES) to obtain the possible pathogenic genes screened in all 3 families. Induced pluripotent stem cells-cardiomyocytes (IPSCs-CMs) were derived and constructed separately from LVNC patients and normal individuals. The cells were collected at different time points and validated by quantitative real-time PCR (qPCR) to observe the expression profiles of above obtained genes during induction and differentiation.

Results

WES screened 14 possible pathogenic genes commonly expressed in the 3 LVNC families. qPCR results suggested that the expression of these genes changed dynamically at different time points (0

20 and 30 d)

and their expression differed significantly from the normal and LVNC patient groups.

Conclusion

There were 14 common possible pathogenic genes screened by WES in the 3 LVNC families

and they are involved in affecting cytoskeleton

cell polarity

calcium and potassium ion regulation and energy metabolism.

关键词

Keywords

references

LIU Y, CHEN H Y, SHOU W N. Potential common pathogenic pathways for the left ventricular noncompaction cardiomyopathy (LVNC)[J]. Pediatr Cardiol, 2018, 39(6): 1099-1106. DOI: 10.1007/s00246-018-1882-z.

UEDA Y, KAMIYA C A, NAKANISHI A, et al . Cardiomyopathy phenotypes and pregnancy outcomes with left ventricular noncompaction cardiomyopathy[J ] . Int Heart J, 2018, 59(4): 862-867. DOI: 10.1536/ihj.17-336.

HIRONO K, HATA Y, NAKAZAWA M, et al . Clinical and echocardiographic impact of tafazzin variants on dilated cardiomyopathy phenotype in left ventricular non-compaction patients in early infancy[J ] . Circ J, 2018, 82(10): 2609-2618. DOI: 10.1253/circj.CJ-18-0470.

TAKASAKI A, HIRONO K, HATA Y, et al . Sarcomere gene variants act as a genetic trigger underlying the development of left ventricular noncompaction[J ] . Pediatr Res, 2018, 84(5): 733-742. DOI: 10.1038/s41390-018-0162-1.

MISZALSKI-JAMKA K, JEFFERIES J L, MAZUR W, et al . Novel genetic triggers and genotype-phenotype correlations in patients with left ventricular noncompaction[J ] . Circ Cardiovasc Ge net, 2017, 10(4): e001763. DOI: 10.1161/CIRCGENETICS.117.001763.

ISHIKAWA T, OHNO S, MURAKAMI T, et al . Sick sinus syndrome with HCN 4 mutations shows early onset and frequent association with atrial fibrillation and left ventricular noncompaction[J ] . Heart Rhythm, 2017, 14(5): 717-724. DOI: 10.1016/j.hrthm.2017.01.020..

ALONSO-FERNÁNDEZ-GATTA M, GALLEGO-DELGADO M, CABALLERO R, et al . A rare HCN 4 variant with combined sinus bradycardia, left atrial dilatation, and hypertrabeculation/left ventricular noncompaction phenotype[J ] . Rev Esp Cardiol (Engl Ed), 2021, 74(9): 781-789. DOI: 10.1016/j.rec.2020.06.019..

TOWBIN J A, LORTS A, JEFFERIES J L. Left ventricular non-compaction cardiomyopathy[J]. Lancet, 2015, 386(9995): 813-825. DOI: 10.1016/s0140-6736(14)61282-4.

TOWBIN J A. Inherited cardiomyopathies[J]. Circ J, 2014, 78(10): 2347-2356. DOI: 10.1253/circj.cj-14-0893.

刘奥怡, 张蕾, 龚梦嘉, 等. 心肌致密化不全患者特异性诱导多潜能干细胞及心肌样细胞的构建[J]. 第三军医大学学报, 2019, 41(24): 2401-2408. DOI: 10.16016/j.1000-5404.201907075.

LIU A Y, ZHANG L, GONG M J, et al . Generation of induced pluripotent stem cells and cardiac myocyte-like cells from a patient with noncompaction of ventricular myocardium[J ] . J Third Mil Med Univ, 2019, 41(24): 2401-2408. DOI: 10.16016/j.1000-5404.201907075.

郭芸, 葛梅, 刘奥怡, 等. 细胞骨架及极性在心肌致密化不全患者来源心肌样细胞中的改变[J]. 第三军医大学学报, 2021, 43(9): 822-829. DOI: 10.16016/j.1000-5404.202011017.

GUO Y, GE M, LIU A Y, et al . Changes of cytoskeleton and polarity in cardiomyocyte-like cells derived from left ventricular noncompaction patients[J ] . J Third Mil Med Univ, 2021, 43(9): 822-829. DOI: 10.16016/j.1000-5404.202011017.

JENNI R, OECHSLIN E, SCHNEIDER J, et al . Echocardiographic and pathoanatomical characteristics of isolated left ventricular non-compaction: a step towards classification as a distinct cardiomyopathy[J ] . Heart 86 (2001) 666-671. DOI: 10.1136/heart.86.6.666

STEFFEN E, PETERSEN, JOSEPH B, et al . Left ventricular non-compaction: insights from cardiovascular magnetic resonance imaging[J ] . Am Coll Cardiol, 2005, 46(1): 101-105. DOI: 10.1016/j.jacc.2005.03.045

UDEOJI D U, PHILIP K J, MORRISSEY R P, et al . Left ventricular noncompaction cardiomyopathy: updated review[J ] . Ther Adv Cardio vasc Dis, 2013, 7(5): 260-273. DOI: 10.1177/1753944713504639.

LOMBARDO B, D'ARGENIO V, MONDA E, et al . Genetic analysis resolves differential diagnosis of a familial syndromic dilated cardiomyopathy: a new case of Alström syndrome[J ] . Mol Genet Genomic Med, 2020, 8(7): e1260. DOI: 10.1002/mgg3.1260.

OSOEGAWA K, IOVANNISCI D M, LIN B, et al . Identification of novel candidate gene loci and increased sex chromosome aneuploidy among infants with conotruncal heart defects[J ] . Am J Med Genet A, 2014, 164A(2): 397-406. DOI: 10.1002/ajmg.a.36291.

ABOU ZIKI M D, BHAT N, NEOGI A, et al . Epistatic interaction of PDE4DIP and DES mutations in familial atrial fibrillation with slow conduction[J ] . Hum Mutat, 2021, 42(10): 1279-1293. DOI: 10.1002/humu.24265.

BUONOCORE F, CLIFFORD-MOBLEY O, KING T F J, et al . Next-generation sequencing reveals novel genetic variants (SRY, DMRT1, NR5A1, DHH, DHX37) in adults with 46, XY DSD[J ] . J Endocr Soc, 2019, 3(12): 2341-2360. DOI: 10.1210/js.2019-00306.

KISS B, GOHLKE J, TONINO P, et al . Nebulin and Lmod2 are c ritical for specifying thin-filament length in skeletal muscle[J ] . Sci Adv, 2020, 6(46): eabc1992. DOI: 10.1126/sciadv.abc1992.

BLANCARD M, DEBBICHE A, KATO K, et al . A loss-of-function CACNA1C variant, p. T1787M, associated with risk of ventricular fibrillation in Africans[J ] . Arch Cardiovasc Dis Suppl, 2018, 10(2): 194.DOI: 10.1016/j.acvdsp.2018.02.042.

HANCOX J C, WHITTAKER D G, DU C Y, et al . Emerging therapeutic targets in the short QT syndrome[J ] . Expert Opin Ther Targets, 2018, 22(5): 439-451. DOI: 10.1080/14728222.2018.1470621.

ZHENG A H, CAO L, QIN S, et al . Exenatide regulates substrate preferences through the p38γ MAPK pathway after ischaemia/reperfusion injury in a rat heart[J ] . Heart Lung Circ, 2017, 26(4): 404-412. DOI: 10.1016/j.hlc.2016.07.006.

FU F, DENG Q, LEI T Y, et al . Clinical application of SNP array analysis in fetuses with ventricular septal defects and normal karyotypes[J ] . Arch Gynecol Obstet, 2017, 296(5): 929-940. DOI: 10.1007/s00404-017-4518-2.

RAO-BHATIA A, ZHU M, YIN W C, et al . Hedgehog-activated Fat 4 and PCP pathways mediate mesenchymal cell clustering and villus formation in gut development[J ] . Dev Cell, 2020, 52(5): 647-658. e6. DOI: 10.1016/j.devcel.2020.02.003.

VAN WIJNGAARDEN A L, HIEMSTRA Y L, KOOPMANN T T, et al . Identification of known and unknown genes associated with mitral valve prolapse using an exome slice methodology[J ] . J Med Genet, 2020, 57(12): 843-850. DOI: 10.1136/jmedgenet-2019-106715.

BOHNEN M S, MA L J, ZHU N, et al . Loss-of-function ABCC 8 mutations in pulmonary arterial hypertension[J ] . Circ Genom Precis Med, 2018, 11(10): e002087. DOI: 10.1161/CIRCGEN.118.002087..

STRUTYNSKYI R B, VORONKOV L G, NAGIBIN V S, et al . Changes of the echocardiographic parameters in chronic heart failure patients with Ile337val, Glu23lys, and Ser1369ala polymorphisms of genes encoding the ATP-sensitive potassium channels subunits in the Ukrainian population[J ] . Ann Hum Genet, 2018, 82(5): 272-279. DOI: 10.1111/ahg.12250.

SONG Y, AHN J, SUH Y, et al . Identification of novel tissue-specific genes by analysis of microarray databases: a human and mouse model[J ] . PLoS One, 2013, 8(5): e64483. DOI: 10.1371/journal.pone.0064483.

LIU L, HUANG J J, LIU Y, et al . Multiomics analysis of transcriptome, epigenome, and genome uncovers putative mechanisms for dilated cardiomyopathy[J ] . Biomed Res Int, 2021, 2021: 6653802. DOI: 10.1155/2021/6653802.

LEE S R, MUN J Y, JEONG M S, et al . Thymoquinone-induced tristetraprolin inhibits tumor growth and metastasis through destabilization of MUC 4 mRNA[J ] . Int J Mol Sci, 2019, 20(11): E2614. DOI: 10.3390/ijms20112614..

BAZRAFSHAN S, KUSHLAF H, KAKROO M, et al . Genetic modifiers of hereditary neuromuscular disorders and cardiomyopathy[J ] . Cells, 2021, 10(2): 349. DOI: 10.3390/cells10020349.

WIGGS J L. CPAMD8, a new gene for anterior segment dysgenesis and childhood glaucoma[J]. Ophthalmology, 2020, 127(6): 767-768. DOI: 10.1016/j.ophtha.2020.02.035.

VILLANUEVA A, BISWAS P, KISHABA K, et al . Identification of the genetic determinants responsible for retinal degeneration in families of Mexican descent[J ] . Ophthalmic Genet, 2018, 39(1): 73-79. DOI: 10.1080/13816810.2017.1373830.

MAURIAC S A, GÉLÉOC G S G. A hop, skip, and a jump to evade USH2A deaf-blindness mutations[J]. Mol Ther, 2021, 29(8): 2391-2393. DOI: 10.1016/j.ymthe.2021.07.008.

ZHAO M, TANG Y W, ZHOU Y, et al . Deciphering Role of Wnt Signalling in Cardiac Mesoderm and Cardiomyocyte Differentiation from Human iPSCs: four-dimensional control of Wnt pathway for hiPSC-CMs differentiation[J ] . Sci Rep, 2019, 9(1): 19389. DOI: 10.1038/s41598-019-55620-x.

ZHANG X Y, YE L, XU H, et al . NRF 2 is required for structural and metabolic maturation of human induced pluripotent stem cell-derived ardiomyocytes[J ] . Stem Cell Res Ther, 2021, 12(1): 208. DOI:10.1186/s13287-021-02264-2..

浏览量

下载量

CSCD

文章被引用时，请邮件提醒。

提交

工具集

关联资源

细胞骨架及极性在心肌致密化不全患者来源心肌样细胞中的改变

靶向Hsp90β的siRNA对Jurkat细胞生长的抑制作用