A novel missense variant c.G644A (p.G215E) of the RPGR gene in a Chinese family causes X-linked retinitis pigmentosa
A novel missense variant c.G644A (p.G215E) of the RPGR gene in a Chinese family causes X-linked retinitis pigmentosa
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DOI：
10.1042/bsr20192235
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发表时间：
2019-10
影响因子：
4
通讯作者：
Jiewen Fu;Jingliang Cheng;Qi Zhou;Chunli Wei;Hanchun Chen;H. Lv;Junjiang Fu
中科院分区：
文献类型：
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作者：
Jiewen Fu;Jingliang Cheng;Qi Zhou;Chunli Wei;Hanchun Chen;H. Lv;Junjiang Fu
摘要X连锁视网膜色素变性（xlRP）的基因突变在中国人群中尚未得到很好的描述。本研究以一个五代中国人视网膜色素变性（RP）家系为研究对象，采用下一代靶向测序（TGS）技术鉴定致病基因，并采用桑格测序技术进行共分离分析。应用RNA-seq数据分析和逆转录-聚合酶链反应（RT-PCR）技术研究人RPGR和小鼠Rpgr基因的表达模式。先证者X染色体RPGR基因（NM_000328.2）第7外显子存在一个新的半合子错义突变体c.G644A（p.G215E），与该家系的临床表型共分离。RNA-seq数据显示，RPGR在27种人体组织中普遍表达，其中睾丸最高，但没有眼组织数据。然后，进行了Rpgr mRNA在小鼠包括眼组织中的表达，结果显示Rpgr转录物在视网膜和睾丸中普遍非常高地表达，并且在其他眼组织包括透镜、巩膜和角膜中高表达;并且在视网膜组织的六个不同发育时期中高表达。RPGR在眼的不同组织中普遍表达，在视网膜中表达非常高，表明RPGR在眼功能中起重要作用，特别是在视网膜中。总之，我们的研究首次表明RPGR基因中的新错义变体c.G644A（p.G215E）可能是该xlRP家族中的致病突变，扩大了突变谱。这些发现有助于更好地了解这种疾病的分子发病机制，为遗传咨询和医疗保健提供新的见解。
Abstract The mutations in patients with X-linked retinitis pigmentosa (xlRP) have not been well described in the Chinese population. In the present study, a five-generation Chinese retinitis pigmentosa (RP) family was recruited; targeted next-generation sequencing (TGS) was used to identify causative genes and Sanger sequencing for co-segregation. RNA-seq data analysis and revere transcriptional-polymerase chain reaction (RT-PCR) were applied to investigate gene expression patterns of RP GTPase regulator (RPGR) in human and Rpgr in mouse. A novel, hemizygous, deleterious and missense variant: c.G644A (p.G215E) in the RPGR gene (NM_000328.2) exon 7 of X-chromosome was identified in the proband, which was co-segregated with the clinical phenotypes in this family. RNA-seq data showed that RPGR is ubiquitously expressed in 27 human tissues with testis in highest, but no eye tissues data. Then the expressions for Rpgr mRNA in mice including eye tissues were conducted and showed that Rpgr transcript is ubiquitously expressed very highly in retina and testis, and highly in other eye tissues including lens, sclera, and cornea; and expressed highly in the six different developmental times of retinal tissue. Ubiquitous expression in different tissues from eye and very high expression in the retina indicated that RPGR plays a vital role in eye functions, particularly in retina. In conclusion, our study is the first to indicate that the novel missense variant c.G644A (p.G215E) in the RPGR gene might be the disease-causing mutation in this xlRP family, expanding mutation spectrum. These findings facilitate better understanding of the molecular pathogenesis of this disease; provide new insights for genetic counseling and healthcare.