Abstract：
Dilated cardiomyopathy (DCM), characterized by left ventricular or biventricular enlargement with systolic dysfunction, is the most common type of cardiac muscle disease. It is a major cause of congestive heart failure and the most frequent indication for heart transplantation. Aggregating evidence has convincingly demonstrated that DCM has an underlying genetic basis, though the genetic defects responsible for DCM in a larger proportion of cases remain elusive, motivating the ongoing research for new DCM-causative genes. In the current investigation, a multigenerational family affected with autosomal-dominant DCM was recruited from the Chinese Han population. By whole-exome sequencing and Sanger sequencing analyses of the DNAs from the family members, a new BMP10 variation, NM_014482.3:c.166C > T;p.(Gln56*), was discovered and verified to be in co-segregation with the DCM phenotype in the entire family. The heterozygous BMP10 variant was not detected in 268 healthy volunteers enrolled as control subjects. The functional measurement via dual-luciferase reporter assay revealed that Gln56*-mutant BMP10 lost the ability to transactivate its target genes NKX2.5 and TBX20, two genes that had been causally linked to DCM. The findings strongly indicate BMP10 as a new gene contributing to DCM in humans and support BMP10 haploinsufficiency as an alternative pathogenic mechanism underpinning DCM, implying potential implications for the early genetic diagnosis and precision prophylaxis of DCM.
摘要：
扩张型心肌病（DCM），以左心室或双心室扩大伴收缩功能障碍为特征，是最常见的心肌疾病。它是充血性心力衰竭的主要原因，也是心脏移植最常见的指征。聚集的证据令人信服地表明，DCM具有潜在的遗传基础，尽管在更大比例的病例中导致DCM的遗传缺陷仍然难以捉摸，推动正在进行的新的DCM致病基因研究。在目前的调查中,从中国汉族人群中招募了一个患有常染色体显性遗传性DCM的多代家庭。通过对家族成员DNA的全外显子组测序和Sanger测序分析，一个新的BMP10变体，NM_014482.3：c.166C>T;p。(Gln56*),在整个家族中发现并证实与DCM表型共分离。在作为对照受试者登记的268名健康志愿者中未检测到杂合BMP10变体。通过双荧光素酶报告基因测定的功能测量显示,Gln56*-突变体BMP10失去了反式激活其靶基因NKX2.5和TBX20的能力,这两个基因与DCM有因果关系。研究结果强烈表明BMP10是导致人类DCM的新基因，并支持BMP10单倍体功能不足作为支撑DCM的替代致病机制。暗示对DCM的早期遗传诊断和精确预防的潜在意义。
