Congenital Achromatopsia and Macular Atrophy Caused by a Novel Recessive PDE6C Mutation (p.E591K)
Congenital Achromatopsia and Macular Atrophy Caused by a Novel Recessive PDE6C Mutation (p.E591K)
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DOI：
10.3109/13816810.2014.991932
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发表时间：
2015-06-01
影响因子：
1.2
通讯作者：
Iwata, Takeshi
中科院分区：
文献类型：
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作者：
Katagiri, Satoshi;Hayashi, Takaaki;Iwata, Takeshi
目的：我们之前报道了两个兄弟姐妹的临床特征，一个姐妹患有完全色盲（ACHM），一个兄弟患有不完全ACHM，在一个日本近亲家庭。在目前的研究中，我们打算在兄弟姐妹中确定一种致病突变，并调查为什么兄弟姐妹的表型不同。方法：对患儿兄弟姐妹及父母进行全面眼科检查。对基因组DNA进行全外显子组和Sanger测序。分子模型分析在二氧化硅研究。结果：眼科检查发现，年龄较大的女同胞在30岁时出现重度黄斑萎缩，弟弟在26岁时出现轻度黄斑萎缩。遗传分析确定了一种新的纯合子PDE6C突变（p.E591K）作为兄弟姐妹中的致病等位基因。每个亲本对突变都是杂合的。分子模拟表明，该突变可引起PDE6C蛋白的构象改变，导致磷酸二酯酶活性降低。我们还发现了一个OPN1SW突变（p.G79R），在妹妹和父亲中，但在兄弟中没有发现，这与先天性tritan缺乏症有关。结论：一种新的纯合子PDE6C突变被确定为导致ACHM的原因。此外，我们在患有完全ACHM的兄弟姐妹中发现了一个OPN1SW突变，这可能解释了兄弟姐妹之间表型（完全与不完全ACHM）的差异。
Purpose: We have previously reported clinical features of two siblings, a sister with complete achromatopsia (ACHM) and a brother with incomplete ACHM, in a consanguineous Japanese family. With the current study, we intended to identify a disease-causing mutation in the siblings and to investigate why the phenotypes of the siblings differed.Methods: We performed a comprehensive ophthalmic examination for each sibling and parent. Whole-exome and Sanger sequencing were performed on genomic DNA. Molecular modeling was analyzed in an in silica study.Results: The ophthalmic examination revealed severe macular atrophy in the older female sibling at 30 years of age and mild macular atrophy in the brother at 26 years of age. The genetic analysis identified a novel homozygous PDE6C mutation (p.E591K) as the disease-causing allele in the siblings. Each parent was heterozygous for the mutation. Molecular modeling showed that the mutation could cause a conformational change in the PDE6C protein and result in reduced phosphodiesterase activity. We also identified an OPN1SW mutation (p.G79R), which is associated with congenital tritan deficiencies, in the sister and the father but not in the brother.Conclusions: A novel homozygous PDE6C mutation was identified as the cause of ACHM. In addition, we identified an OPN1SW mutation in the sibling with complete ACHM, which might explain the difference in phenotype (complete versus incomplete ACHM) between the siblings.