Department of Paediatric Surgery, Human Genetics, Ophthalmology and McGill Ocular Genetics Laboratory, McGill University Health Center Research Institute, Montreal, Quebec, Canada.
Molecular Vision, Hillsboro, OR, USA.
Sci Rep. 2018 Mar 22;8(1):5034. doi: 10.1038/s41598-018-22704-z.
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.
CRX 是一种转录因子，对于激活许多光感受器神经元基因的表达是必需的。CRX 可能在三种形式的人类失明中发生突变：先天性黑蒙（LCA）、圆锥杆状细胞变性（CRD）和色素性视网膜炎（RP）。在大多数情况下，致病机制可能是显性负作用，具有功能获得。我们报告了一种新的、完全纯合的 CRX 缺失，发生在 LCA 中。我们鉴定了一个具有 3 例 LCA 受累的黎巴嫩家族。先证者通过 NGS 进行了测序。进行了定量 PCR、阵列比较基因组杂交和长距离 PCR。进行了全面的眼部检查、OCT 和摄影。我们鉴定出 CRX 的一个纯合的 56000bp 缺失，它与 4 位父母的杂合子共分离，这些父母报告视力正常。患有 LCA 的盲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 的一个拷贝（单倍体不足）导致轻度异常的中心凹发育，但不会导致 LCA。两位父母的内、外中心凹和光感受器有明显的异常。这是首例报道的纯合、完全 CRX 缺失的病例。CRX 的纯合子缺失导致 LCA，而 CRX 的单倍体不足导致中心凹发育异常，但不会导致 LCA。我们的数据为 CRX 提供了一种新的疾病机制。
