A Homozygous Missense Mutation in NEUROD1 Is Associated With Nonsyndromic Autosomal Recessive Retinitis Pigmentosa
A Homozygous Missense Mutation in NEUROD1 Is Associated With Nonsyndromic Autosomal Recessive Retinitis Pigmentosa
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DOI：
10.1167/iovs.14-15382
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发表时间：
2015-01-01
影响因子：
4.4
通讯作者：
Chen, Rui
中科院分区：
文献类型：
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作者：
Wang, Feng;Li, Huajin;Chen, Rui
目的.同一基因的突变可导致不同的临床表型。本研究旨在通过分析一个未解决的常染色体隐性遗传性视网膜色素变性（ARRP）汉族家系，寻找新的基因型-表型相关性和新的致病基因。对一个ARRP家系先证者进行全外显子组测序。应用严格的变体过滤和优先排序来鉴定致病突变。NEUROD 1中的纯合错义变体c.724G>A; p.V242I被确定为最可能的病因。该等位基因在家族中完全分离，并影响在哺乳动物中高度保守的氨基酸。先前的研究表明，NEUROD 1中的纯合无效等位基因导致严重的新生儿糖尿病综合征疾病、系统性神经系统异常和早发性视网膜营养不良。与这些结果一致，我们的错义等位基因不太严重的纯合子患者仅表现为迟发性视网膜变性，没有任何综合征性视网膜变性。我们确定了NEUROD 1和非综合征型ARRP之间潜在的新基因型-表型相关性。我们的研究支持NEUROD 1对维持视网膜功能很重要的观点，NEUROD 1的部分功能缺失突变可能是非综合征型ARRP的罕见原因。
PURPOSE. Mutations in the same gene can lead to different clinical phenotypes. In this study, we aim to identify novel genotype-phenotype correlations and novel disease genes by analyzing an unsolved autosomal recessive retinitis pigmentosa (ARRP) Han Chinese family.METHODS. Whole exome sequencing was performed for one proband from the consanguineous ARRP family. Stringent variants filtering and prioritizations were applied to identify the causative mutation.RESULTS. A homozygous missense variant, c.724G>A; p.V242I, in NEUROD1 was identified as the most likely cause of disease. This allele perfectly segregates in the family and affects an amino acid, which is highly conserved among mammals. A previous study showed that a homozygous null allele in NEUROD1 causes severe syndromic disease with neonatal diabetes, systematic neurological abnormalities, and early-onset retinal dystrophy. Consistent with these results, our patients who are homozygous for a less severe missense allele presented only late-onset retinal degeneration without any syndromic symptoms.CONCLUSIONS. We identified a potential novel genotype-phenotype correlation between NEUROD1 and nonsyndromic ARRP. Our study supports the idea that NEUROD1 is important for maintenance of the retina function and partial loss-of-function mutation in NEUROD1 is likely a rare cause of nonsyndromic ARRP.