右位心基因LRRC56鉴定和遗传缺陷小鼠模型构建

Dextrocardia refers to the right-sided heart, which can occur in an isolated fashion or as a symptom of syndrome. It can coexist with other situs inversus and cardiac malformation. Dextrocardia with other situs inversus usually include right-sided spleen and stomach, and left-sided liver and gall bladder. Genetic and environmental factors are proposed to be responsible for dextrocardia, and it is usually characterized by autosomal recessive inheritance. Syndromic dextrocardia is involved in many syndromes, referring to primary ciliary dyskinesia, nephronophthisis, polycystic kidney disease 2, and Bardet-Biedl syndrome, etc. More than 30 disease-causing genes for syndromic dextrocardia have been identified. Most of genetic studies involved in dextrocardia pay close attention to syndromic dextrocardia. In our preliminary study, a novel disease-causing gene LRRC56 mutation was identified in a dextrocardia family, and the constructed lrrc56 knock-down zebrafish may partially mimic the phenotypes of the disorder. In this study, the mutation frequency of the LRRC56 gene in dextrocardia will be defined. The mechanism of lrrc56-caused dextrocardia will be studied using lrrc56 knock-down zebrafish. Construction of Lrrc56 mutant knock-in mouse model mimics human mutation to a greater extent and further reveal the pathogenic mechanism for dextrocardia.

右位心(dextrocardia)是指心脏在胸腔右侧，可单独出现或表现为综合征组成部分，可合并其它内脏转位及心脏畸形。右位心伴其它内脏转位通常包括右位脾、右位胃、左位肝和左位胆囊。右位心可能涉及遗传和环境因素，一般认为主要呈常染色体隐性遗传。综合征性右位心涉及原发性纤毛运动障碍、肾消耗病、2型多囊肾病和Bardet-Biedl综合征等多种综合征，已鉴定超过30个致病基因。大多数右位心基因研究密切关注综合征性右位心。我们前期在一个右位心家系中发现新的致病LRRC56基因突变，构建的lrrc56基因敲减斑马鱼模型能部分模拟疾病表型。本研究拟明确LRRC56基因在右位心及其它内脏转位中的发生频率，应用lrrc56基因敲减斑马鱼模型研究lrrc56导致右位心机制，并进一步构建Lrrc56基因突变敲入小鼠模型，更大程度模拟人类突变，进一步解析右位心的疾病发生机制。

右位心(dextrocardia)是指心脏在胸腔的位置移向右侧，可单独出现，也可表现为综合征的组成部分，可合并其它内脏转位及心脏畸形。右位心伴其它内脏转位通常包括右位脾、右位胃、左位肝和左位胆囊。每6000-8000个新生儿中约有一例存在内脏转位。右位心可能涉及遗传和环境因素，一般认为主要呈常染色体隐性遗传。综合征性右位心涉及原发性纤毛运动障碍、肾消耗病、2型多囊肾病和Bardet-Biedl综合征等多种综合征，已鉴定超过30个致病基因。大多数右位心基因研究密切关注综合征性右位心，特别是原发性纤毛运动障碍综合征，但只占20%-25%的右位心病例。我们前期应用外显子组测序和Sanger测序鉴定了右位心基因LRRC56，构建的lrrc56基因敲减斑马鱼模型能部分模拟疾病表型。本研究进一步明确了LRRC56基因变异在右位心及其它内脏转位中的发生频率，应用全外显子组测序分析筛选获得了新右位心基因及变异。已鉴定了5个新的右位心基因及13个家系的基因变异。通过细胞实验和构建基因敲减斑马鱼和Lrrc56基因突变敲入小鼠模型，有助于解析包括右位心在内的单纯性及综合征性内脏转位的疾病发生机制。