Understanding the molecular mechanisms of human microtia via a pig model of HOXA1 syndrome.
Understanding the molecular mechanisms of human microtia via a pig model of HOXA1 syndrome.
复制标题
通过 HOXA1 综合征猪模型了解人类小耳畸形的分子机制
DOI：
10.1242/dmm.018291
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发表时间：
2015-06
影响因子：
4.3
通讯作者：
Ren J
中科院分区：
文献类型：
--
作者：
Qiao R;He Y;Pan B;Xiao S;Zhang X;Li J;Zhang Z;Hong Y;Xing Y;Ren J
小耳畸形是外耳的一种先天性畸形。尽管小耳畸形与遗传和环境因素都有关，但这种先天性疾病的遗传病因了解甚少。猪会自然发生与人类相似的疾病，为剖析人类遗传性疾病的分子机制提供了绝佳机会。在此我们首先证明，HOXA1基因的截断突变导致猪的单基因小耳畸形疾病。我们进一步对患病和健康的猪胚胎（第14.25天）进行了RNA测序（RNA - Seq）分析。我们确定了正常样本和突变样本之间的337个差异表达基因（DEGs），这为涉及HOXA1的转录网络提供了线索。这些差异表达基因在与心血管系统和胚胎发育以及神经、肾脏和泌尿系统疾病相关的生物学过程中富集。许多差异表达基因的异常表达与人类小耳相关综合征对应的先天性畸形有关。应用三种优先级算法后，我们从337个差异表达基因中突出了人类小耳畸形的有吸引力的候选基因。我们在147名小耳畸形患者的六个候选基因中寻找具有功能重要性的编码变异。值得注意的是，我们确定了一个EVC2非同义突变（p.Asp1174Asn）作为一种人类小耳相关综合征的潜在致病变异。这些发现增进了我们对人类小耳畸形分子机制的理解，并提供了一个利用猪模型表征人类疾病易感变异的有趣实例。
总结：HOXA1综合征的猪模型为人类小耳畸形的分子机制提供了新的见解。
ABSTRACT Microtia is a congenital malformation of the outer ears. Although both genetic and environmental components have been implicated in microtia, the genetic causes of this innate disorder are poorly understood. Pigs have naturally occurring diseases comparable to those in humans, providing exceptional opportunity to dissect the molecular mechanism of human inherited diseases. Here we first demonstrated that a truncating mutation in HOXA1 causes a monogenic disorder of microtia in pigs. We further performed RNA sequencing (RNA-Seq) analysis on affected and healthy pig embryos (day 14.25). We identified a list of 337 differentially expressed genes (DEGs) between the normal and mutant samples, shedding light on the transcriptional network involving HOXA1. The DEGs are enriched in biological processes related to cardiovascular system and embryonic development, and neurological, renal and urological diseases. Aberrant expressions of many DEGs have been implicated in human innate deformities corresponding to microtia-associated syndromes. After applying three prioritizing algorithms, we highlighted appealing candidate genes for human microtia from the 337 DEGs. We searched for coding variants of functional significance within six candidate genes in 147 microtia-affected individuals. Of note, we identified one EVC2 non-synonymous mutation (p.Asp1174Asn) as a potential disease-implicating variant for a human microtia-associated syndrome. The findings advance our understanding of the molecular mechanisms underlying human microtia, and provide an interesting example of the characterization of human disease-predisposing variants using pig models. Summary: A pig model of HOXA1 syndrome provides novel insight into the molecular mechanisms of human microtia.
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