PDF(Sci-hub)
Abstract：
HOX genes are important regulatory genes patterning head formation, including development of the ear. Microtia is a congenital ear anomaly characterized by lacking all or part of the structures of the outer ear. To date, only four HOXA2 mutations were reported in families with autosomal-recessive or dominant microtia, with or without hearing impairment. More identified mutations are needed to confirm the correlation between genotype and phenotype. Here, we collect two Chinese families with non-syndromic bilateral microtia. Next generation sequencing identified two heterozygous nonsense HOXA2 mutations, one in each family. One mutation (c.637A > T, p.Lys213*) is newly reported, while the other one (c.703C > T,p.Gln235*) is consistent with a previous report. In mouse, Hoxa2 can bind to a long-range enhancer and regulate expression of the Hmx1 gene, which is a crucial transcription factor in eye and ear development. Using dual luciferase reporter assays, we showed that both HOXA2 mutations have impaired activation of the long-range enhancer of HMX1. In the present study, we report the first two bilateral non-syndromic microtia cases with HOXA2 mutations of Chinese origin and identify a novel mutation. Our results also provide molecular insights about how these nonsense HOXA2 mutations could affect the activation of its downstream target HMX1 by interacting with the long-range enhancer.
摘要：
HOX基因是头型形成的重要调控基因,包括耳朵的发育。小耳畸形是一种先天性耳异常，其特征是缺乏外耳的全部或部分结构。迄今为止,仅有4个HOXA2突变在常染色体隐性遗传或显性小耳畸形的家庭中报告，有或没有听力障碍。需要更多鉴定的突变来确认基因型和表型之间的相关性。这里,我们收集了两个患有非综合征性双侧小耳畸形的中国家庭。下一代测序确定了两个杂合无义HOXA2突变，每个家庭都有一个。一个突变（c.637A>T，p.Lys213*)是新报道的，而另一个(c.703C>T，P.Gln235*)与以前的报告一致。在老鼠身上,Hoxa2可以与长程增强子结合并调节Hmx1基因的表达，它是眼和耳发育中至关重要的转录因子。使用双荧光素酶报告基因测定，我们发现两种HOXA2突变都损害了HMX1的长程增强子的激活。在本研究中,我们报告了前两例双侧非综合征型小耳畸形病例,其中HOXA2突变为中国血统,并鉴定了一个新的突变.我们的结果还提供了有关这些无义HOXA2突变如何通过与长程增强子相互作用影响其下游靶标HMX1活化的分子见解。
