Identification of two novel mutations in CDHR1 in consanguineous Spanish families with autosomal recessive retinal dystrophy.
Identification of two novel mutations in CDHR1 in consanguineous Spanish families with autosomal recessive retinal dystrophy.
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DOI：
10.1038/srep13902
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发表时间：
2015-09-09
影响因子：
4.6
通讯作者：
Ayuso C
中科院分区：
文献类型：
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作者：
Nikopoulos K;Avila-Fernandez A;Corton M;Lopez-Molina MI;Perez-Carro R;Bontadelli L;Di Gioia SA;Zurita O;Garcia-Sandoval B;Rivolta C;Ayuso C
遗传性视网膜营养不良表现出广泛的表型和遗传异质性，给患者的分子和临床诊断带来了挑战。在这项研究中，我们想要对两个西班牙近亲家庭的非典型常染色体隐性视网膜营养不良进行临床表征和分子病因学研究。各个家族的受影响成员表现出一系列临床特征，包括视力下降、畏光、色觉缺陷、ERG 反应减少或缺失、黄斑萎缩和周边视网膜色素沉积。在第一个家族中，遗传研究包括自合性作图和外显子组测序，而在第二个家族中，通过桑格 DNA 测序进行自合子引导的候选基因筛选。我们的方法揭示了 CDHR1 中的核苷酸变化；纯合错义变体（c.1720C > G，p.P574A）和纯合单碱基转换（c.1485 + 2T > C）分别影响内含子13的规范5'剪接位点。这两种变化与疾病共同分离，并且在不相关的对照个体队列中不存在。迄今为止，仅发现了 CDHR1 的 5 个突变，所有突变都会导致终止密码子过早出现，从而导致 mRNA 无义介导的衰变。我们的工作报告了 CDHR1 中两个先前未识别的纯合突变，进一步扩大了该基因的突变谱。
Inherited retinal dystrophies present extensive phenotypic and genetic heterogeneity, posing a challenge for patients’ molecular and clinical diagnoses. In this study, we wanted to clinically characterize and investigate the molecular etiology of an atypical form of autosomal recessive retinal dystrophy in two consanguineous Spanish families. Affected members of the respective families exhibited an array of clinical features including reduced visual acuity, photophobia, defective color vision, reduced or absent ERG responses, macular atrophy and pigmentary deposits in the peripheral retina. Genetic investigation included autozygosity mapping coupled with exome sequencing in the first family, whereas autozygome-guided candidate gene screening was performed by means of Sanger DNA sequencing in the second family. Our approach revealed nucleotide changes in CDHR1; a homozygous missense variant (c.1720C > G, p.P574A) and a homozygous single base transition (c.1485 + 2T > C) affecting the canonical 5’ splice site of intron 13, respectively. Both changes co-segregated with the disease and were absent among cohorts of unrelated control individuals. To date, only five mutations in CDHR1 have been identified, all resulting in premature stop codons leading to mRNA nonsense mediated decay. Our work reports two previously unidentified homozygous mutations in CDHR1 further expanding the mutational spectrum of this gene.