Milam Ann H, Rose Linda, Cideciyan Artur V, Barakat Mark R, Tang Wai-Xing, Gupta Nisha, Aleman Tomas S, Wright Alan F, Stone Edwin M, Sheffield Val C, Jacobson Samuel G
Scheie Eye Institute and F. M. Kirby Center for Molecular Ophthalmology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Proc Natl Acad Sci U S A. 2002 Jan 8;99(1):473-8. doi: 10.1073/pnas.022533099. Epub 2002 Jan 2.
Normal human retinal development involves orderly generation of rods and cones by complex mechanisms. Cell-fate specification involves progenitor cell lineage and external signals such as soluble factors and cell-cell interactions. In most inherited human retinal degenerations, including retinitis pigmentosa, a mutant gene causes loss of visual function, death of mature rods, and eventually death of all cone subtypes. Only one inherited retinal disorder, the enhanced S cone syndrome (ESCS), shows increased visual function, involving the minority S (blue) cones, and decreased rod and L/M (red/green) cone function. This autosomal recessive disease is caused by mutations in NR2E3, a photoreceptor nuclear receptor transcription factor, and may result from abnormal cell-fate determination, leading to excess S cones at the expense of other photoreceptor subtypes. In 16 ESCS patients with the most common NR2E3 mutation, R311Q, we documented an abnormal ratio of S to L/M cone function and progressive retinal degeneration. We studied the postmortem retina of an ESCS patient homozygous for NR2E3 R311Q. No rods were identified, but cones were increased approximately 2-fold, and 92% were S cones. Only 15% of the cones expressed L/M cone opsin, and some coexpressed S cone opsin. The retina was disorganized, with densely packed cones intermixed with inner retinal neurons. The retina was also degenerate, retaining photoreceptors in only the central and far peripheral regions. These observations suggest a key role for NR2E3 in regulation of human photoreceptor development. Degeneration of the NR2E3 retina may result from defective development, known S cone fragility, or abnormal maintenance of mature photoreceptors.
正常人类视网膜发育涉及通过复杂机制有序生成视杆细胞和视锥细胞。细胞命运特化涉及祖细胞谱系以及可溶性因子和细胞间相互作用等外部信号。在大多数遗传性人类视网膜变性中，包括色素性视网膜炎，一个突变基因会导致视觉功能丧失、成熟视杆细胞死亡，并最终导致所有视锥细胞亚型死亡。只有一种遗传性视网膜疾病，即增强型S视锥细胞综合征（ESCS），显示视觉功能增强，涉及少数S（蓝色）视锥细胞，而视杆细胞和L/M（红色/绿色）视锥细胞功能下降。这种常染色体隐性疾病是由光感受器核受体转录因子NR2E3的突变引起的，可能是由于异常的细胞命运决定，导致以牺牲其他光感受器亚型为代价而产生过多的S视锥细胞。在16名患有最常见NR2E3突变R311Q的ESCS患者中，我们记录了S视锥细胞与L/M视锥细胞功能的异常比例以及进行性视网膜变性。我们研究了一名NR2E3 R311Q纯合的ESCS患者的死后视网膜。未发现视杆细胞，但视锥细胞增加了约2倍，且92%为S视锥细胞。只有15%的视锥细胞表达L/M视锥细胞视蛋白，一些还共表达S视锥细胞视蛋白。视网膜结构紊乱，密集排列的视锥细胞与视网膜内层神经元混合在一起。视网膜也发生了退化，仅在中央和远周边区域保留了光感受器。这些观察结果表明NR2E3在人类光感受器发育调控中起关键作用。NR2E3视网膜的退化可能是由于发育缺陷、已知的S视锥细胞脆弱性或成熟光感受器的异常维持所致。
