摘要
研究背景
左室心肌致密化不全心肌病(Left ventricular noncompaction, LVNC)是一种罕见的原发型遗传性心肌病,以心室内存在粗大的肌小梁和深陷隐窝为主要特征,又称为海绵状心肌。本病可单独发生,称为孤立的心室肌致密化不全(IVNM),有时也合并其他先天性心脏病,如Ebstein畸形,房室间隔缺损等。迄今为止,导致疾病的原因不明。一般认为,心肌在胚胎发育过程中,由于各种原因导致心肌致密化过程失败,肌小梁异常粗大,未被吸收,导致小梁隐窝持续存在。临床主要表现为进行性心力衰竭,心律失常,陈旧性附壁血栓和猝死。
家系遗传调查发现,该疾病以常染色体显性遗传为主,有时也表现为X-连锁遗传和线粒体遗传。已有的分子遗传学研究发现了一些编码肌小节的基因(MYH7, ACTC, MYBPC3, TNNT2),细胞骨架蛋白基因(ZASP, LMNA)以及线粒体蛋白基因(TAZ)可能与LVNC有关系,但是并不能完全解释所有LVNC的发病机制。基于前人的工作,我们推测LVNC的病因或许与线粒体、心肌胚胎发育过程有关。因而,结合传统的研究手段,扩大候选基因筛选范围,从整个基因组的水平对LVNC进行研究,寻找LVNC的真正致病原因。
研究目的
利用分子生物学、分子遗传学和高通量测序技术,结合临床和病理特征,探寻LVNC的分子遗传学发病机制。寻找致病原因,为临床诊断和治疗提供依据和方向。
研究方法和结果
1)家系分析和组织病理学研究
对入选的典型LVNC患者的心肌组织标本进行病理学水平研究,发现部分患者心肌组织肌丝排列疏松,心肌间存在严重的纤维化,但是并没有发现特异的共同的病理学表现；心肌组织均存在凋亡现象,患者心肌组织有异常分化现象；心肌组织增殖检测呈阴性。透射电镜结果显示,左室心肌组织肌小节溶解,线粒体结构和定位异常。
2)对六例LVNC患者左室心肌组织的线粒体基因组进行研究
提取LVNC患者的线粒体DNA进行全测序,发现227个异常变异,其中157个位于编码区,70个位于非编码区,其中位于MT-CO3的m.9856T>C突变保守系数较高(0.88),但是通过家系分析,排除了作为候选致病基因的可能；利用长PCR片段扩增技术检测患者mtDNA,没有发现mtDNA有大片段的序列缺失或重复：利用real-time PCR技术对mtDNA的拷贝数变化进行研究,结果表明,LVNC患者组心肌mtDNA拷贝数为3840±226.5,正常组心肌mtDNA拷贝数为8266±900.8,P<0.01, LVNC患者心肌mtDNA拷贝数较正常组低。
3)全外显子组研究
利用高通量测序技术对四例典型的LVNC患者(IVNC)的基因组DNA进行全外显子组测序,结合临床资料和病理研究,进行生物信息学分析,寻找候选基因。经过分析发现,除了发现编码肌小节蛋白TNNT2、MYBPC3等突变之外,还发现了核编码线粒体蛋白的突变,以及信号通路上的突变。Wnt信号通路异常可能与LVNC的发生有关系。
结论
通过对典型的LVNC样本的研究发现患者的心肌组织大量凋亡,且存在异常分化现象；患者组心肌线粒体DNA拷贝数降低,心肌的超微结构显示肌纤维紊乱和线粒体结构异常,提示患者心肌线粒体功能异常。这些是患者发生心力衰竭的原因,但并不是LVNC发生的直接原因；全外显子组测序后结合生物信息学分析发现,LVNC的发生可能与调控胚胎期心脏发育的Wnt信号通路异常有关。
增加研究样本量和进一步的功能实验研究将有助于揭示LVNC的真正致病原因。
Rational
LVNC is a rare primary genetic heart disease, characterized by numerous prominent trabeculars and deep intertrabecular recesses in left ventricular. It was previously termed "spongy myocardium" although this term has been abandoned because it underscores the hypothesis that the basic morphogenetic abnormality may be arrest of normal compaction of the loose interwoven mesh of myocardial fibers in the embryo. LVNC may be an isolated finding in the absence of any coexisting cardiac anomaly, called isolated ventricular noncompaction (IVNM),or may be associated with other congenital anomalies, such as Ebstein malformation, ventricular septal defect etc. It is widely accepted that LVNC is caused by noncompaction of the myocardium during embryonic development. The genetic basis of this cardiomyopathy is still largely unsolved and mechanism of the disease remains unclear. The heterogenetiy of the clinical features includes both asymptomatic and symptomatic patients with progressive deterioration in cardiac function that results in congestive heart failure, arrhythmias, thromboembolic events, and sudden cardiac death.
Clinical study suggested that LVNC is often familiar with predominantly autosomal domiant inheritance. X-linked recessive inheritance and mitochondrion inheritance of neonatal LVNC also have been described. It has been linked to mutations in genes including sarcomere component (MYH7, ACTC, MYBPC3, TNNT2), cytoskeletal protein (ZASP, LMNA) and TAZ (G4.5). However, mutants in all of the above mentioned genes account for only a small percentage of patients. And mutations in the genes encoding sarcomere proteins have been associated with both hypertrophic and dilated cardiomyopathy. In addition, LVNC happened with neuromuscular diseases such as Barth syndrome. G4.5is a candidate gene for Barth syndrome, encoding a metabolism related phosphatide protein which is located in mitochondria. Based on all of these preceding works, we hypothesized that the pathology of LVNC maybe associated with mitochondria or/and abnormalities in development of myocardiocytes. Thus, expanding the scope of candidate gene scanning, even from the whole genome level, may be an effective way to uncover the pathogeny of LVNC.
Aims The present study was undertaken to investigate the molecular genetic basis of LVNC by using technologies of molecular biology, molecular genetics, and high throughput sequencing.
Methods and Results
1) Pedigree counseling and histopathology investigation
Pathologic study of LVNC patients' myocardium reaveled that, myofilament in some patients'myocardium were loosely arranged and severe fibrosis existed between myocardium. However, no common characteristic of pathology was found. Apoptosis exists in all of the four myocardium samples with some myocardium differentiation possitive; No proliferation of myocardium was found. Results from transmission electron microscope showed that, left ventricular myocardial tissue sarcomere was dissolved, and the structure and location of mitochondria was abnormal.
2) The investigation to mitochondrial DNA from6LVNC patients
The patients' mitochondrial genomic DNA (mtDNA) of LVNC were extracted and sequenced.227abnormal variations were found, among which157variations localized in coding region and70variants localized in non-coding region. Mutant conservative index of m.9856T>C in MT-CO3localized in MT-CO3was high, however, it was excluded from candidated disease-causing gene after pedigree analysis; Results from long segment PCR amplification technology showed that, mtDNA in LVNC myocardium was3840±226.5, lowered than that of normal myocardium (8266±900.8, P<0.01).
3) Whole exome sequencing
Whole exome sequencing was performed by high-throughput sequencing technologies in four patients with typical LVNC (IVNC). Bioinformatics analysis combined with clinical data and pathologic study reaveled that, abnomalities in Wnt signaling pathway may be one of the causes of LVNC.
Conclusions
Although there was no consistent pathological characteristics in six LVNC myocardium specimens, muscle fiber disorders and abnormal mitochondria ultrastructure observed by transmission electron microscope suggested that mitochondria dysfunction; Whole exome sequencing analysis revealed that, LVNC may be associated with abnormalities of cell signaling pathway during embryonic heart development. More information might have been found if the patient number were larger and further function studies of mutation genes are needed to reveal the true etiology of LVNC.
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