Liu Song, Bi Jian Gang, Hu Yunlong, Tang Donge, Li Bo, Zhu Peng, Peng Wujian, Du Dong, He Huiyan, Zeng Jun, Dai Yong
Clinical Medical Research Center, The Second Clinical Medical College of Jinan University (Shenzhen People's Hospital), Shenzhen, Guangdong, R.P. China.
Department of Hepatobiliary Surgery, The Second Medical College of Jinan University (Shenzhen People's Hospital), Shenzhen, China.
Mol Genet Genomic Med. 2019 Apr;7(4):e00577. doi: 10.1002/mgg3.577. Epub 2019 Feb 20.
Retinitis pigmentosa (RP) is one of the major types of hereditary retinal dystrophies with extreme genotypic heterogeneity. To date, more than 80 genes have been identified to be associated with RP in human.
Here, we presented a clinical genetic study of three Chinese man manifested with night vision blindness and complete loss of midperipheral visual field. All of these three probands have been identified with loss of both central vision and far peripheral visual field. Gradual loss of rod cells followed by subsequent loss of cone cells have been identified in these probands. Targeted next generation sequencing and Sanger sequencing have been performed to understand the pathogenic variants underlying the disease phenotype in these three unrelated Chinese probands.
Targeted next generation sequencing and Sanger sequencing identified three homozygous novel mutations (c.1880C>A; c.1459_1460delGA, and c.392G>A) in the MERTK gene in these three unrelated Chinese proband. In the first proband, the identified mutation (c.1880C>A) leads to the formation of a premature stop codon followed by the formation of a truncated mer-tyrosine kinase (MERTK) protein (p.Ser627*) product which predicted to be disease causing. In the second proband, the identified deletion (c.1459_1460delGA) leads to the formation of a frameshift which also finally results in the formation of a truncated MERTK protein (p.Asp487Leufs57) product which also predicted to be disease causing. In the third proband, the identified mutation (c.392G>A) leads to the formation of a premature stop codon followed by the formation of a truncated MERTK protein (p.Trp131) product which also predicted to be disease causing. Hence, these three mutations are loss-of-function mutations. These three mutations were absent in unaffected family members and in 100 normal healthy controls.
Our present study also demonstrates the significance of targeted next generation sequencing in determining the genetic basis of RP.
视网膜色素变性（RP）是遗传性视网膜营养不良的主要类型之一，具有极高的基因异质性。迄今为止，已确定超过80个基因与人类RP相关。
在此，我们对三名表现为夜盲和中周边视野完全丧失的中国男性进行了临床遗传学研究。这三名先证者均已被确定为中心视力和远周边视野丧失。在这些先证者中已发现视杆细胞逐渐丧失，随后视锥细胞丧失。进行了靶向二代测序和桑格测序，以了解这三名不相关的中国先证者疾病表型背后的致病变异。
靶向二代测序和桑格测序在这三名不相关的中国先证者的MERTK基因中鉴定出三个纯合新突变（c.1880C>A；c.1459_1460delGA和c.392G>A）。在第一个先证者中，鉴定出的突变（c.1880C>A）导致形成一个提前终止密码子，随后形成截短的mer-酪氨酸激酶（MERTK）蛋白（p.Ser627*）产物，预计该产物具有致病作用。在第二个先证者中，鉴定出的缺失（c.1459_1460delGA）导致移码，最终也导致形成截短的MERTK蛋白（p.Asp487Leufs57）产物，预计该产物也具有致病作用。在第三个先证者中，鉴定出的突变（c.392G>A）导致形成一个提前终止密码子，随后形成截短的MERTK蛋白（p.Trp131）产物，预计该产物也具有致病作用。因此，这三个突变均为功能丧失性突变。这三个突变在未受影响的家庭成员和100名正常健康对照中均不存在。
我们目前的研究还证明了靶向二代测序在确定RP遗传基础方面的重要性。
