A rare genomic duplication in 2p14 underlies autosomal dominant hearing loss DFNA58.
A rare genomic duplication in 2p14 underlies autosomal dominant hearing loss DFNA58.
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DOI：
10.1093/hmg/ddaa075
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发表时间：
2020-04
影响因子：
3.5
通讯作者：
Karina Lezirovitz;G. A. Vieira-Silva;A. C. Batissoco;D. Levy;J. Kitajima;Alix Trouillet;Ellen Ouyang-
中科院分区：
文献类型：
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作者：
Karina Lezirovitz;G. A. Vieira-Silva;A. C. Batissoco;D. Levy;J. Kitajima;Alix Trouillet;Ellen Ouyang-
在这里，我们将2p14中约200 Kb的基因组重复定义为2009年首次报道的DFNA 58家族20名受影响个体中与舌后进行性感音神经性常染色体显性听力损失分离的遗传标记。重复包括两个完整的基因，PLEK和CNRIP1，和PPP3R1（蛋白质编码）的第一个外显子，除了四个未知的长非编码（lnc）RNA基因和一个新的蛋白质编码基因的一部分。血液样本中mRNA表达的定量分析显示，CNRIP1和两个lncRNA基因（LOC107985892和LOC102724389）的选择性过表达在所有受影响的成员测试，但不是在未受影响的。mRNA表达的定性分析也确定了融合转录涉及PPP3R1，CNRIP1和PLEK和CNRIP1之间的基因间区域的部分，在血液中的所有载体的重复，但在性质上是异质的。通过原位杂交和免疫荧光，我们发现Cnrip1，Plek和Ppp3r1基因都在成年小鼠耳蜗包括螺旋神经节神经元中表达，这表明这些基因在听觉器官中表达水平的变化可能是DFNA 58型耳聋的基础。我们的研究强调了研究导致听力损失的罕见基因组事件（例如拷贝数变异）的价值。需要进一步的研究来确定这些基因中的哪一个，无论是编码蛋白还是非编码RNA，都是DFNA 58听力损失的原因。
Here we define a ~ 200Kb genomic duplication in 2p14 as the genetic signature that segregates with post-lingual progressive sensorineural autosomal dominant hearing loss in 20 affected individuals from the DFNA58 family, first reported in 2009. The duplication includes two entire genes, PLEK and CNRIP1, and the first exon of PPP3R1 (protein-coding), in addition to four uncharacterized long noncoding (lnc) RNA genes and part of a novel protein-coding gene. Quantitative analysis of mRNA expression in blood samples revealed selective overexpression of CNRIP1 and of two lncRNA genes (LOC107985892 and LOC102724389) in all affected members tested, but not in unaffected ones. Qualitative analysis of mRNA expression identified also fusion transcripts involving parts of PPP3R1, CNRIP1 and an intergenic region between PLEK and CNRIP1, in the blood of all carriers of the duplication, but were heterogeneous in nature. By in situ hybridization and immunofluorescence, we showed that Cnrip1, Plek and Ppp3r1 genes are all expressed in the adult mouse cochlea including the spiral ganglion neurons, suggesting changes in expression levels of these genes in the hearing organ could underlie the DFNA58 form of deafness. Our study highlights the value of studying rare genomic events leading to hearing loss such as copy number variations. Further studies will be required to determine which of these genes, either coding proteins or non-coding RNAs, is or are responsible for DFNA58 hearing loss.