A complete, homozygous CRX deletion causing nullizygosity is a new genetic mechanism for Leber congenital amaurosis.
A complete, homozygous CRX deletion causing nullizygosity is a new genetic mechanism for Leber congenital amaurosis.
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DOI：
10.1038/s41598-018-22704-z
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发表时间：
2018-03-22
影响因子：
4.6
通讯作者：
Koenekoop RK
中科院分区：
文献类型：
--
作者：
Ibrahim MT;Alarcon-Martinez T;Lopez I;Fajardo N;Chiang J;Koenekoop RK
CRX是激活许多光感受器神经元基因表达所需的转录因子。CRX可能在人类失明的三种形式中发生突变; Leber先天性黑蒙（LCA）、视锥-视杆变性（CRD）和视网膜色素变性（RP）。在大多数情况下，致病机制可能是显性负性的，具有功能增益。我们报告了一种新的，完全纯合CRX缺失LCA。我们发现一个黎巴嫩家庭有3例受影响的LCA病例。先证者经NGS测序。进行定量PCR、阵列比较基因组杂交和远程PCR。进行了全面的眼部检查、OCT和摄影。我们鉴定了CRX的56，000 bp纯合缺失，其在四个报告视力正常的父母中共分离并杂合。患有LCA的失明儿童表现出严重的视网膜变性，这是CRX和LCA的典型表型。我们假设CRX（单倍不足）的单拷贝导致轻度异常的中心凹发育，而不是LCA。父母有显着的内，外凹和感光异常。这是第一个纯合子，完全CRX缺失的报告病例。CRX的非合性导致LCA，而CRX的单倍性不足导致异常的中央凹发育，但不是LCA。我们的数据表明CRX的一种新的发病机制。
CRX is a transcription factor required for activating the expression of many photoreceptor-neuron genes. CRX may be mutated in three forms of human blindness; Leber congenital amaurosis (LCA), cone-rod degeneration (CRD) and retinitis pigmentosa (RP). The pathogenic mechanism in most cases is likely dominant negative, with gain of function. We report a novel, complete homozygous CRX deletion in LCA. We identified a Lebanese family with 3 affected LCA cases. The proband was sequenced by NGS. Quantitative PCR, array comparative genomic hybridization, and long range PCR were performed. Full eye examinations, OCT and photography were performed. We identified a homozygous 56,000 bp deletion of CRX, which co-segregates and is heterozygous in four parents, who report normal vision. The blind children with LCA manifest severe retinal degeneration, a phenotype typical for CRX and LCA. We hypothesized that a single copy of CRX (haplo-insufficiency) in the causes mild abnormal foveal development, but not LCA. Two parents had significant inner and outer foveal and photoreceptor abnormalities. This is the first reported case of a homozygous, complete CRX deletion. Nullizygosity of CRX thus causes LCA while haplo-insufficiency of CRX causes abnormal foveal development, but not LCA. Our data suggest a new disease mechanism for CRX.
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